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Cyclin-dependent kinase 5 (Cdk5), which binds to and is activated by p35, phosphorylates multiple substrates and plays an essential role in the development and function of the CNS; however, proteolytic production of p25 from p35 under stress conditions leads to the inappropriate activation of Cdk5 and contributes to hyperphosphorylation of τ and other substrates that are related to the pathogenesis of Alzheimer's disease. Selective inhibition of aberrant Cdk5 activity via genetic overexpression of Cdk5 inhibitory peptide (CIP) reduces pathologic changes and prevents brain atrophy and memory loss in p25-transgenic mice. In the present study, we delivered adeno-associated virus 9 carrying green fluorescent protein CIP (AAV9-GFP-CIP) to brain cells via intracerebroventricular infusion in amyloid precursor protein/presenilin 1 (APP/PS1) double-transgenic 3-mo-old mice after the occurrence of β-amyloid (Aβ) aggregation and the hyperphosphorylation of τ. Three months of treatment of AAV9-GFP-CIP reduced pathologic changes, including τ hyperphosphorylation, (Aβ) deposit, astrocytosis, and microgliosis, which were correlated with the reversal of memory loss and anxiety-like behavior observed in APP/PS1 mice. The neuroprotection effect of AAV9-GFP-CIP lasted an additional 7 mo--the end point of the study. These findings provide a novel strategy to selectively target Cdk5 for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Mitochondrial creatine kinase (MtCK) is vital in the process of mitochondrial energy metabolism, and mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). Therefore, we speculated that MtCK activity could be altered in the serum of PD patients. However, no studies to date have investigated this specific topic, so we sought to investigate the serum MtCK activities among a cohort of PD patients. 50 patients with PD and 30 age-matched controls were recruited for this study. Serum ubiquitous MtCK (uMtCK) and sarcomeric MtCK (sMtCK) activities were assayed using an immunoinhibition method. Correlations between serum uMtCK/sMtCK activities and clinical features/parameters were explored in the PD group. Our study revealed a significant decrease in the uMtCK activity in the PD group when compared with the control group. No significant difference was found in the serum sMtCK activity between the PD and control groups. There was a significant correlation between serum uMtCK activities and the disease progression rate, duration, and age at onset in PD patients. While no significant relationship was found between the serum uMtCK activities and the Hoehn & Yahr stage or main non-motor symptoms scale. There was a significant decrease in the uMtCK activity in the serum of PD patients, which was associated with the rate of disease progression, duration, and age at onset of disease. Therefore, uMtCK activity in serum offers a useful clue for identification of PD biomarkers. [ABSTRACT FROM AUTHOR]

Glibenclamide (GBC) is an antidiabetic drug that is in a class of medications known as sulfonylureas, which play critical roles in attenuating brain edema and reducing mortality in ischemic stroke patients. Therapeutic hypothermia (TH) is another robust neuroprotectant that prevents brain swelling and improves the neurological outcomes of stroke patients. However, whether the combination of GBC and TH can be used as a reliable neuroprotectant in ischemic stroke remains largely unknown. We used the middle cerebral artery occlusion (MCAO) rat model as well as oxygen and glucose deprivation-reoxygenation (OGD/R) endothelial cells as ischemic stroke models to investigate the efficacy and mechanisms of treating ischemic stroke with the combination of GBC and TH. The serum glucose, mortality rate, neurobehavioral functions, tight junctions, endothelial cells and inflammatory cytokines were evaluated in the stroke models after treatment with GBC, TH or the combination of them. After 5-hour occlusion and subsequent reperfusion, rats exhibited a large volume of hemispheric swelling and a high mortality rate. Stroke rats treated with the combined therapy did not exhibit hypoglycemia. The combination of GBC and TH exhibited synergistic neuroprotective effects in stroke rats that were associated with greater reductions in edema volume, better improvement in neurobehavioral functions, prevention of tight junction loss, and reduction of expression of the inflammatory cytokines COX-2 and iNOS. In OGD/R endothelia cells, the combination reduced endothelial cell death. This study demonstrated that both GBC and TH are neuroprotective after the severe stroke; however, combined therapy with GBC and TH enhanced the efficiency and efficacy of the effects of TH and GBC in the treatment of ischemia. This combined therapy may facilitate the clinical translation of TH management for severe stroke. The combination of GBC and TH seems to be a feasible and promising clinical strategy to alleviate cerebral injury following severe stroke. [ABSTRACT FROM AUTHOR]

Objective: It is generally acknowledged that drug dependence is connected with abnormal functional organization in the individual's brain. The present study aimed to identify the anterior cingulate cortex (ACC) abnormality with the cerebral networks involved in betel quid dependence (BQD) by resting-state functional connectivity (rsFC) using functional magnetic resonance imaging (fMRI).Methods: With fMRI data measured from 33 resting-state BQD individuals and 32 non-addicted and age-, sex-, education-matched healthy controls, we inquired into the BQD-related changes in FC between the regions of ACC with the whole brain involved in BQD individuals using a region of interest vised method, and to identify the relation of the alteration with the severity of BQD and duration.Results: Compared to controls, the BQD group showed increased connectivity from ACC to the regions of the reward network (brainstem including midbrain regions such as the ventral tegmental area and pons, caudate, thalamus) and cerebellum. Decreased connectivity was observed in the BQD group in regions from ACC to the default mode network (medial prefrontal cortex and precuneus) and para Hippocampal/hypothalamus. Specifically, the BQD scale was positively correlated with increased FC of right ACC to left thalamus and left ACC to pons; the durations were negatively correlated with FC of right ACC to left precuneus.Conclusion: These disturbances in rsFC from ACC to the reward network and DMN revealed by fMRI may have a key function in providing insights into the neurological pathophysiology underlying BQD-associated executive dysfunction and disinhibition. These findings may contribute to our better understanding of the mechanisms underlying BQD. [ABSTRACT FROM AUTHOR]

Background: Although male predominance was documented in previous studies on cryptococcal meningoencephalitis (CM), there has been no statistical study about female CM patients despite recently noticeable increase in female prevalence. In the current study, we aimed to investigate the independent gender-specific contributing risk factors for onset of CM and factors related to survival time in female patients by chosen statistical tools.Methods: There have been 108 patients diagnosed with CM from July 1, 1998 to June 30, 2013 in Nanfang Hospital that were included in our study. This 15-year retrospective study compared demographic and clinical features of 31 female patients with 77 males. Multivariate analysis was performed for detection of the contributors to the onset of CM in female patients. The independent variables for multivariate analysis were selected according to statistical significance in univariate analysis. Furthermore, Cox regression model was used to evaluate the factors related to survival length.Results: Use of corticosteroids or other immunosuppressants (32.3% versus 11.7%; p = 0.011) and history of systemic lupus erythematosus (SLE) and other autoimmune diseases (29% versus 3.9%; p < 0.001) were more common in females, but only the history of SLE or other autoimmune diseases was significant (OR 10.59, 95% CI 1.49-74.77, p = 0.02) by multivariate analysis. The ratio of cerebrospinal fluid (CSF) glucose-to-blood glucose was related to the survival time (p = 0.03, 95% CI 0-0.71).Conclusions: The results showed that the history of SLE or other autoimmune diseases rather than chronic use of corticosteroids and/or immunosuppressants was the independent gender-specific contributing risk factor in female CM patients. Therefore, more attention should be made to the prevention of infection from the genus Cryptococcus spp. in female patients with SLE or other autoimmune diseases. In addition, decreased ratio of CSF glucose-to-blood glucose before antifungal therapy predicted the worse prognosis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), characterized by β-amyloid deposition and neurodegeneration, is the most common cause of dementia worldwide. Emerging evidence suggests that ectopic expression of micro (mi)RNAs is involved in the pathogenesis of AD. There is increasing evidence that miRNAs expressed in the brain are involved in neuronal development, survival and apoptosis. The expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is regulated by dysregulated miRNAs in the brain. The present study determined the expression levels of the miRNA-29 (miR-29) family in peripheral blood samples of patients with AD and demonstrated a marked decrease in the expression of miR-29c compared with age-matched controls. In addition, a significant increase in the exprssion of BACE1 was observed in the peripheral blood of patients with AD. Correlation analysis revealed that the expression of miR-29c was negatively correlated with the protein expression of BACE1 in the peripheral blood samples from patients with AD. The present study also investigated the role of miR-29 on hippocampal neurons in vitro and in vivo. The results demonstrated that the upregulation of miR-29c promoted learning and memory behaviors in SAMP8 mice, at least partially, by increasing the activity of protein kinase A/cAMP response element-binding protein, involved in neuroprotection. This evidence suggested that miR-29c may be a promising potential therapeutic target against AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the most common form of dementia in the aged population, presents an increasing clinical challenge in terms of diagnosis and treatment. Neurodegeneration is one of the hallmarks of AD, which consequently induces cognitive impairment. Brain-derived neurotrophic factor (BDNF), a neuroprotective factor, has been implicated in neuronal survival and proliferation. The epigenetic mechanism of BDNF methylation may be responsible for the reduced expression of BDNF in patients with AD. DNA methyltransferase may contribute to the methylation of BDNF, which is involved in neuroprotection in AD. In addition, epigenetic modifications, including a combination of microRNAs (miRNAs/miRs) and DNA methylation, have been suggested as regulatory mechanisms in the control of neuronal survival. In the present study, the expression of miR-29c was determined in the cerebrospinal fluid (CSF) of patients with AD and of healthy control individuals. A marked decrease in the expression of miR-29c was observed in the AD group compared with the normal control group, accompanied by a decreased in the expression of BDNF. Additionally, a significant increase in the expression of DNA methyltransferase 3 (DNMT3) was observed in the CSF from the patients with AD. Correlation analysis revealed that the expression of miR-29c was positively correlated with BDNF and negatively correlated with DNMT3 protein in the CSF of patients with AD. In addition, the regulatory association between miR-29c, DNMT3 and BDNF were also examined in vitro. It was demonstrated that miR-29c directly targeted DNMT3 and contributed to neuronal proliferation by regulating the expression of BDNF, at least partially, through enhancing the activity of the tyrosine receptor kinase B/extracellular signal-regulated kinase signaling pathway. In conclusion, the present study suggested that miR-29c may be a promising potential therapeutic target in the treatment of AD. [ABSTRACT FROM AUTHOR]