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The present study aimed to investigate the effects of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway on the Wnt/β-catenin signaling pathway in rats with focal cerebral ischemia-reperfusion injury. A total of 96 rat focal cerebral ischemia-reperfusion models, established according to a modified version of Longa's method, were randomly divided into four groups: Sham-operated (S), cerebral ischemia-reperfusion injury (I), cerebral ischemia-reperfusion + basic fibroblast growth factor (bFGF) post-processing and, finally, cerebral ischemia-reperfusion + bFGF post-processing + PI3K inhibitor LY294002 (LY). Each group consisted of 24 rats and each group was divided into four subgroups according to the indicated reperfusion times of 12, 24, 48 and 72 h. The morphological changes of the cortical tissue and the cellular apoptosis were determined using hematoxylin and eosin staining and the terminal deoxynucleotidyl transferase dUTP nick end labeling method, respectively. The expression levels of phosphorylated (p-)Akt, glycogen synthase kinase-3β (GSK-3β) mRNA and β-catenin in the cortical tissue were detected at different time-points. The number of apoptotic cells and the expression levels of p-Akt, GSK-3β mRNA and β-catenin in the I and LY groups were significantly higher compared with those in the S group (P<0.05). In the bFGF group, the number of apoptotic cells and the mRNA expression levels of GSK-3β were significantly decreased, whereas the expression levels of p-Akt and β-catenin were significantly increased compared with those in the I and LY groups (P<0.05). In cerebral ischemia-reperfusion injury, the PI3K/Akt signaling pathway regulated β-catenin, the main member of the Wnt signaling pathway, via GSK-3β, providing information to assist in further investigation of the mechanism of β-catenin in ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation plays a critical role in the onset and development of neurodegeneration disorders such as Parkinson's disease. The immune activities of the central nervous system are profoundly affected by peripheral immune activities. Immune tolerance refers to the unresponsiveness of the immune system to continuous or repeated stimulation to avoid excessive inflammation and unnecessary by-stander injury in the face of continuous antigen threat. It has been proved that the immune tolerance could suppress the development of various peripheral inflammation-related diseases. However, the role of immune tolerance in neuroinflammation and neurodegenerative diseases was not clear.Methods: Rats were injected with repeated low-dose lipopolysaccharide (LPS, 0.3 mg/kg) intraperitoneally for 4 days to induce peripheral immune tolerance. Neuroinflammation was produced using intracranial LPS (15 μg) injection. Inflammation cytokines were measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Microglial activation were measured using immunostaining of Iba-1 and ED-1. Dopaminergic neuronal damage was evaluated using immunochemistry staining and stereological counting of TH-positive neurons. Behavioral impairment was evaluated using amphetamine-induced rotational behavioral assessment.Results: Compared with the non-immune tolerated animals, pre-treatment of peripheral immune tolerance significantly decreased the production of inflammatory cytokines, suppressed the microglial activation, and increased the number of dopaminergic neuronal survival in the substantia nigra.Conclusions: Our results indicated that peripheral immune tolerance attenuated neuroinflammation and inhibited neuroinflammation-induced dopaminergic neuronal death. [ABSTRACT FROM AUTHOR]

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for Parkinson's disease (PD), the predictive effect of levodopa responsiveness on surgical outcomes was confirmed by some studies. however, there were different conclusions about that through long and short-term follow-ups. We aimed to investigate the factors which influence the predictive value of levodopa responsiveness and discover more predictive factors of surgical outcomes. Methods: Twenty-three PD patients underwent bilateral STN-DBS and completed our follow-up. Clinical evaluations were performed 1 week before and 3 months after surgery. Results: STN-DBS significantly improved motor function of PD patients after 3 months; preoperative levodopa responsiveness and disease subtype predicted the effect of DBS on motor function; gender disease duration and duration of motor fluctuations modified the predictive effect of levodopa responsiveness on motor improvement; the duration of motor fluctuations and severity of preoperative motor symptoms modified the predictive effect of disease subtype on motor improvement. Conclusions: The intensity of levodopa responsiveness served as a predictor of motor improvement more accurately in female patients, patients with shorter disease duration or shorter motor fluctuations; PD patients with dominant axial symptoms benefit less from STN-DBS compared to those with limb-predominant symptoms, especially in their later disease stage. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disorder, which is characterized by the selective and progressive death of dopaminergic (DA) neurons in the substantia nigra. Increasing evidence suggests that inflammation is important in the degeneration of DA neurons. The purinergic receptor subtype P2X7 receptor (P2X7R) is key in the activation and proliferation of microglia. The present study aimed to examine whether inhibiting purinergic P2X7 receptors is neuroprotective in a rat model of PD, specifically via inhibiting p38 mitogen-activated protein kinase (MAPK). In an intranigral lipopolysaccharide (LPS) rat model of PD, immunohistochemical analysis revealed enhanced expression of P2X7R was observed in microglia. The administration of the P2X7R antagonist, brilliant blue G (BBG), reduced activation of the microglia and the loss of nigral DA neurons. In addition, immunohistochemistry and western blot analysis revealed the phosphorylation level of p38 MAPK increased in the microglia of the LPS-injected rats, which was inhibited by BBG treatment. The p38 MAPK inhibitor, SB203580, reduced microglial activation and the loss of DA neurons. Thus, these findings suggested that inhibition of P2X7R by BBG attenuated microglial activation and the loss of substantia nigra DA neurons via p38 MAPK in the rat LPS model of PD. [ABSTRACT FROM AUTHOR]

Dendritic cells and CD8+ T cells participate in the pathology of chronic obstructive pulmonary disease, including emphysema, but little is known of the involvement of the CD40/CD40L pathway. We investigated the role of the CD40/CD40L pathway in Tc1 cell differentiation induced by dendritic cells in a mouse model of emphysema, and in vitro. C57BL/6J wild-type and CD40-/- mice were exposed to cigarette smoke (CS) or not (control), for 24 wk. In vitro experiments involved wild-type and CD40-/- dendritic cells treated with CS extract (CSE) or not. Compared with the control groups, the CS mice (both wild type and CD40-/-) had a greater percentage of lung dendritic cells and higher levels of major histocompatability complex (MHC) class I molecules and costimulatory molecules CD40 and CD80. Relative to the CS CD40-/- mice, the CS wild type showed greater signs of lung damage and Tc1 cell differentiation. In vitro, the CSE-treated wild-type cells evidenced more cytokine release (IL-12/p70) and Tc1 cell differentiation than did the CSE-treated CD40-/- cells. Exposure to cigarette smoke increases the percentage of lung dendritic cells and promotes Tc1 cell differentiation via the CD40/CD40L pathway. Blocking the CD40/ CD40L pathway may suppress development of emphysema in mice exposed to cigarette smoke. [ABSTRACT FROM AUTHOR]

Background: Fatigue, which is commonly observed in Parkinson's disease (PD), can greatly reduce quality of life and is difficult to treat. We here aimed to investigate the prevalence and characteristics of fatigue among PD patients and to explore an effective strategy to treat PD fatigue. Method: This was an observational cross-sectional study conducted in northeastern China. We examined fatigue in 222 PD patients from northeastern China using the Parkinson Fatigue Scale-16 (PFS-16). The disease severity, depression, sleep and cognitive functioning were assessed with the Hoehn & Yahr staging (H-Y stage), Unified Parkinson's Disease Rating Scale (UPDRS), Hamilton Depression Scale (HAMD), Parkinson's Disease Sleep Scale (PDSS) and Montreal Cognitive Assessment (MoCA) by interview. Results: The frequency of fatigue in PD patients was 59.46%. Fatigued patients had longer disease durations and greater disease severity than nonfatigued patients. Additionally, fatigued PD patients scored significantly higher for all motor symptoms, except for tremor, and had more serious depressive symptoms and sleep disturbances than nonfatigued PD patients did. The sleep disturbance severity was an independent factor for fatigue. Furthermore, 43.04% of fatigued patients taking dopaminergic drugs had fatigue remission. Depression severity was identified as an independent factor for dopaminergic drug non-responsive fatigue. Conclusions: PD patients with severe sleep disturbances tend to suffer from fatigue. Levodopa improved fatigue only in PD patients with mild depression or no depression, implying that dopaminergic medication is required, but not sufficient, for fatigue suppression in PD patients with moderate or severe depression. Thus, restoring serotonergic neurotransmission as a combination therapy may offer a better strategy for the treatment of fatigue in these patients. [ABSTRACT FROM AUTHOR]

Phorbol myristate acetate (PMA), as a potent tumor promoter, may induce microglial senescence. The present study investigated the effect of PMA infection on microglial senescence. From 58 male Sprague-Dawley rats, 10 were randomly selected and divided into a PMA injection group, containing five rats (0.5 μg/μl PMA) and a control group, containing five rats (commensurable 0.9% saline). Immunofluorescent staining of Iba-1 and enzyme-linked immunosorbent assay analyses of the expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1 β were performed in these two groups. The remaining 48 rats were randomly divided into the following three groups, each containing 16 rats: Repeated injection control group (commensurable normal saline, once a week for 4 weeks), single PMA injection group (0.5 μg/μl PMA, once in the first week) and repeated injection PMA group (0.5 μg/μl PMA, once a week for 4 weeks). The expression levels of p21, detected using double immunofluorescence staining with Iba-1, and β-galactosidase, via double immunohistochemical staining of Iba-1, were examined in these three groups. The results indicated that a single injection of PMA did not change the microglial morphology and had no significant effects on the expression levels of TNF-α and IL-1β, compared with the control group (P>0.05). Following four repeated injections of PMA, the microglia in the substantia nigra presented with features of senescence, characterized by increased expression levels of β-galactosidase (P<0.001) and p21 (P<0.001), compared with the repeated injection control group. In conclusion, repeated intra-nigrostriatal treatment with PMA induced microglial senescence with increased expression levels of β-galactosidase and p21 in the substantia nigra of the rats. [ABSTRACT FROM AUTHOR]

Corticosteroid insensitivity, which is induced by cigarette smoke extract (CSE), is a significant barrier when treating chronic obstructive pulmonary disease (COPD). Erythromycin (EM) has been shown to have an anti-inflammatory role in some chronic airway inflammatory diseases, particularly diffuse panbronchiolitis and cystic fibrosis. Here, we explored whether the combination therapy of EM and dexamethasone (Dex) reverses corticosteroid insensitivity and investigated the molecular mechanism by which this occurs. We demonstrated that the combination of EM and Dex restored corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from COPD patients and U937 cells after CSE exposure. Moreover, pretreatment with 10, 50, or 100 μg/ml EM reversed the HDAC2 protein reduction induced by CSE exposure in a dose-dependent manner. U937 cells exposed to CSE show a reduction in histone deacetylase (HDAC) activity, which was potently reversed by EM or combination treatment. Although 10 and 17.5% CSE increased phosphorylated Akt (PAkt) expression in a concentration-dependent manner, preapplication of EM and the combination treatment in particular blocked this PAkt increase. Total Akt levels were unaffected by CSE or EM treatments. Furthermore, the combination treatment enhanced glucocorticoid receptor (GR)α expression. Our results demonstrate that the combination therapy of EM and Dex can restore corticosteroid sensitivity through inhibition of the PI3K-δ/Akt pathway and enhancing GRα expression. [ABSTRACT FROM AUTHOR]

Background: Language impairment is relatively common in Parkinson's disease (PD), but not all PD patients are susceptible to language problems. In this study, we identified among a sample of PD patients those pre-disposed to language impairment, describe their clinical profiles, and consider factors that may precipitate language disability in these patients. Methods: A cross-sectional cohort of 31 PD patients and 20 controls were administered the Chinese version of the Western Aphasia Battery (WAB) to assess language abilities, and the Montreal Cognitive Assessment (MoCA) to determine cognitive status. PD patients were then apportioned to a language-impaired PD (LI-PD) group or a PD group with no language impairment (NLI-PD). Performance on the WAB and MoCA was investigated for correlation with the aphasia quotient deterioration rate (AQDR). Results: The PD patients scored significantly lower on most of the WAB subtests than did the controls. The aphasia quotient, cortical quotient, and spontaneous speech and naming subtests of the WAB were significantly different between LI-PD and NLI-PD groups. The AQDR scores significantly and positively correlated with age at onset and motor function deterioration. Conclusion: A subset group was susceptible to language dysfunction, a major deficit in spontaneous speech. Once established, dysphasia progression is closely associated with age at onset and motor disability progression. [ABSTRACT FROM AUTHOR]

Background: Language impairment is relatively common in Parkinson's disease (PD), but not all PD patients are susceptible to language problems. In this study, we identified among a sample of PD patients those pre-disposed to language impairment, describe their clinical profiles, and consider factors that may precipitate language disability in these patients. Methods: A cross-sectional cohort of 31 PD patients and 20 controls were administered the Chinese version of the Western Aphasia Battery (WAB) to assess language abilities, and the Montreal Cognitive Assessment (MoCA) to determine cognitive status. PD patients were then apportioned to a language-impaired PD (LI-PD) group or a PD group with no language impairment (NLI-PD). Performance on the WAB and MoCA was investigated for correlation with the aphasia quotient deterioration rate (AQDR). Results: The PD patients scored significantly lower on most of the WAB subtests than did the controls. The aphasia quotient, cortical quotient, and spontaneous speech and naming subtests of the WAB were significantly different between LI-PD and NLI-PD groups. The AQDR scores significantly and positively correlated with age at onset and motor function deterioration. Conclusion: A subset group was susceptible to language dysfunction, a major deficit in spontaneous speech. Once established, dysphasia progression is closely associated with age at onset and motor disability progression. [ABSTRACT FROM AUTHOR]

Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays an important role in the pathophysiology of atherosclerosis and thrombosis. This study is aimed at evaluating the potential association of 3’- UTR-C188T and G501C in LOX-1 gene with cerebral infarction. Methods: A total of 386 patients with cerebral infarction and 386 healthy controls were included in the study, which were unrelated Chinese Han population in the Liaoning Province of northern China. The single nucleotide polymorphisms, 3’-UTR-C188T and G501C, were analyzed by polymerase chain reaction–ligation detection reaction method. Results: The frequencies of CC + GC genotype, GC genotype and C allele of G501C in the patients with cerebral infarction were significantly higher than those in the controls (P < 0.01, P < 0.01, P = 0.04, respectively). The correlation still remained after adjusting for confounding risk factors of cerebral infarction. In addition, no significant association was observed between 3’-UTR-C188T and cerebral infarction. Conclusions: The study indicated that the G501C variant in LOX-1 gene may be associated with susceptibility to cerebral infarction, independent of other common risk factors, in northern Chinese Han population. [ABSTRACT FROM AUTHOR]

Heavy smoking can induce airway inflammation and emphysema. Macrolides can modulate inflammation and effector T-cell response in the lungs. However, there is no information on whether erythromycin can modulate regulatory T-cell (Treg) response. This study is aimed at examining the impact of erythromycin on Treg response in the lungs in a rat model of smoking-induced emphysema. Male Wistar rats were exposed to normal air or cigarette smoking daily for 12 weeks and treated by gavage with 100 mg/kg of erythromycin or saline daily beginning at the forth week for nine weeks. The lung inflammation and the numbers of inflammatory infiltrates in bronchoalveolar lavage fluid (BALF) were characterized. The frequency, the number of Tregs, and the levels of Foxp3 expression in the lungs and IL-8, IL-35, and TNF-α in BALF were determined by flow cytometry, RT-PCR and ELISA, respectively. Treatment with erythromycin reduced smoking-induced inflammatory infiltrates, the levels of IL-8 and TNF-α in the BALF and lung damages but increased the numbers of CD4+Foxp3+ Tregs and the levels of Foxp3 transcription in the lungs, accompanied by increased levels of IL-35 in the BALF of rats. Our novel data indicated that erythromycin enhanced Treg responses, associated with the inhibition of smoking-induced inflammation in the lungs of rats. [ABSTRACT FROM AUTHOR]

Background/Aims: Cognitive impairment (CI) is common in Parkinson’s disease (PD), and the cognitive deterioration rate (CDR) is heterogeneous among PD patients. However, very few studies have reported on the association of PD features and risk factors with rapid CDR. The Montreal Cognitive Assessment (MoCA) is considered to be a sensitive and reliable approach to detect mild CI. In the present study, we sought to define and compare the cognitive profiles and clinical features of PD patients with slow or rapid CDRs, and then to identify the PD risk factors associated with rapid CDR. Methods: A cross-sectional study of cognitive rate was performed using the MoCA in a cohort of 73 PD patients and 41 controls matched for age, sex and education level. Results: The rapid CDR group was characterized by older age (58.8 years in slow CDR vs. 64.1 in rapid CDR; p = 0.02), later age at disease onset (52.7 vs. 61.7 years; p < 0.001), a faster deterioration rate of movement symptoms (UPDRS III increment of 12.8 vs. 5.9/year; p < 0.001), a higher rate in multiple-domain CI (38.9 vs. 10.8%), and generally lower MoCA subscores for the Clock Drawing Test, attention, verbal fluency and abstraction. According to the univariate logistic regression model, onset age, movement deterioration rate, multiple domains CI and executive function CI were risk factors for rapid CDR. However, only the movement deterioration rate (p = 0.01) and onset age (p = 0.05) remained independent predictors for rapid CDR according to the multivariate logistic regression model. Conclusions: The CI deterioration in a subset of PD patients appears to progress more rapidly. Identifying those PD patients may not only help to predict the development of PD dementia, but also facilitate therapeutic intervention at early disease stages. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]