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Zhou S.,Chongqing Medical University | Zhou R.,Chongqing Medical University | Zhong T.,Chongqing Medical University | Li R.,Chongqing Medical University | And 2 more authors.
Current Alzheimer Research | Year: 2014

Background: Previous studies relating smoking and alcohol drinking with the incidence of dementia have been inconsistent. Objectives: We assessed whether smoking and alcohol drinking was associated with the risk of dementia, including Alzheimer disease (AD) and vascular dementia (VaD) after seven years of follow-up. Design: We prospectively analysed the incidence of dementia from 2004 to 2011 among 2959 elderly men, according to their smoking and alcohol drinking status. Setting: six neighbourhoods from three districts mentioned in Chongqing city. Participants: A total of 3170 men were followed up annually for 7 years. Measurements: Cox proportional hazards models were established to evaluate the association between smoking, alcohol drinking and the risk of dementia. Results: The incidences of AD and VaD were higher respectively in current smoking than never smoking, daily drinking than never drinking over 7 years of follow-up (p<0.01). After adjusting for age and other potential confounders, current smoking was associated with increased risk of AD (HR= 2.14, 95% CI 1.20-4.46) and VaD (HR= 3.28, 95% CI 1.14-4.52), meanwhile, daily drinking was related to increased risk of AD (HR= 2.25, 95% CI 1.43-3.97) and VaD (HR= 3.42, 95% CI 1.18-4.51). In addition, co-smoking and drinking were related to with a significantly higher risk of AD and VaD than non-smoking and drinking (HR= 3.03, 95% CI 1.65-4.19) and VaD (HR= 3.96, 95% CI 1.64-4.71). Moreover, co-smoking and drinking had higher risk of AD and VaD compared with current smoking and daily drinking. Conclusions: Current smoking and daily drinking were found to be significantly associated with dementia in elderly men. © 2014 Bentham Science Publishers. Source

Bailey A.R.,Silver Child Development Center | Hou H.,Silver Child Development Center | Obregon D.F.,Silver Child Development Center | Tian J.,Silver Child Development Center | And 7 more authors.
FASEB Journal | Year: 2012

Abnormalities in T-lymphocyte populations and function are observed in autism. Soluble amyloid precursor protein α (sAPP-α) is elevated in some patients with autism and is known to be produced by immune cells. In light of the well-established role of sAPP-α in proliferation, growth, and survival of neurons, we hypothesized an analogous role in the immune system. Thus, we explored whether sAPP-α could modulate immune development and function, especially aspects of the pinnacle cell of the adaptive arm of the immune system: the T cell. To do this, we generated mice overexpressing human sAPP-α and characterized elements of T-cell development, signal transduction, cytokine production, and innate/adaptive immune functions. Here, we report that transgenic sAPP-α-overexpressing (TgsAPP-α) mice displayed increased proportions of CD8 + T cells, while effector memory T cells were decreased in the thymus. Overall apoptotic signal transduction was decreased in the thymus, an effect that correlated with dramatic elevations in Notch1 activation; while active-caspase-3/total-caspase-3 and Bax/Bcl-2 ratios were decreased. Greater levels of IFN-γ, IL-2, and IL-4 were observed after ex vivo challenge of TgsAPP-α mouse splenocytes with T-cell mitogen. Finally, after immunization, splenocytes from TgsAPP-α mice displayed decreased levels IFN-γ, IL-2, and IL-4, as well as suppressed ZAP70 activation, after recall antigen stimulation. Given elevated levels of circulating sAPP-α in some patients with autism, sAPP-α could potentially drive aspects of immune dysfunction observed in these patients, including dysregulated T-cell apoptosis, aberrant PI3K/AKT signaling, cytokine alterations, and impaired T-cell recall stimulation. © FASEB. Source

Liu Y.-H.,Chongqing Medical University | Zeng F.,Chongqing Medical University | Wang Y.-R.,Chongqing Medical University | Zhou H.-D.,Chongqing Medical University | And 3 more authors.
Drug Discovery Today | Year: 2013

Alzheimer's disease (AD) is the most common neurodegenerative disorder among older people. However, no cure or disease-modifying treatments are currently available, and the molecular and cellular mechanisms responsible for the etiology of AD remain under debate. Recent studies suggest that the immune system has a crucial role in AD pathogenesis and, thus, immunotherapy might be a promising new treatment. Here, we review the roles of the immune system in AD pathogenesis as well as recent developments in immunotherapy for AD. Furthermore, we hypothesize that age-related immune dysregulation, which might be a consequence of the age-associated chronic inflammation known as 'inflammaging', significantly contributes to AD pathogenesis. Finally, we propose various immunological mechanisms for the development of safe and effective therapies for AD. © 2013 Elsevier Ltd. All rights reserved. Source

Mori T.,Saitama University | Koyama N.,Saitama University | Segawa T.,Immuno Biological Laboratories Co. | Maeda M.,Immuno Biological Laboratories Co. | And 6 more authors.
Journal of Biological Chemistry | Year: 2014

Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in the brains of patients with Alzheimer disease (AD). Here, we tested whether the experimental agent methylene blue (MB), used for treatment of methemoglobinemia, might improve AD-like pathology and behavioral deficits. We orally administered MB to the aged transgenic PSAPP mouse model of cerebral amyloidosis and evaluated cognitive function and cerebral amyloid pathology. Beginning at 15 months of age, animals were gavaged with MB (3 mg/kg) or vehicle once daily for 3 months. MB treatment significantly prevented transgeneassociated behavioral impairment, including hyperactivity, decreased object recognition, and defective spatial working and reference memory, but it did not alter nontransgenic mouse behavior. Moreover, brain parenchymal and cerebral vascular β-amyloid deposits as well as levels of various Aβ species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, β-carboxyl-terminal APP fragment and β-site APP cleaving enzyme 1 protein expression and activity were attenuated. Additionally, treatment of Chinese hamster ovary cells overexpressing human wild-type APP with MB significantly decreased Aβ production and amyloidogenic APP proteolysis. These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Smith A.J.,University of South Florida | Smith A.J.,Silver Child Development Center | Kavuru P.,University of South Florida | Wojtas L.,University of South Florida | And 3 more authors.
Molecular Pharmaceutics | Year: 2011

Flavonoids have been studied extensively due to the observation that diets rich in these compounds are associated with lower incidences of many diseases. One of the most studied flavonoids, quercetin, is also the most abundant of these compounds in the plant kingdom. Numerous therapeutic bioactivities have been identified in vitro. However, its in vivo efficacy in pure form is limited by poor bioavailability, primarily due to its low solubility and consequent low absorption in the gut. Cocrystallization has gained attention recently as a means for improving the physicochemical characteristics of a compound. Here, we synthesized and evaluated four new cocrystals of quercetin (QUE): quercetin:caffeine (QUECAF), quercetin:caffeine:methanol (QUECAF·MeOH), quercetin:isonicotinamide (QUEINM), and quercetin:theobromine dihydrate (QUETBR·2H 2O). Each of these cocrystals exhibited pharmacokinetic properties that are vastly superior to those of quercetin alone. Cocrystallization was able to overcome the water insolubility of quercetin, with all four cocrystals exhibiting some degree of solubility. The QUECAF and QUECAF·MeOH cocrystals increased the solubility of QUE by 14- and 8-fold when compared to QUE dihydrate. We hypothesized that this improved solubility would translate into enhanced systemic absorption of QUE. This hypothesis was supported in our pharmacokinetic study. The cocrystals outperformed QUE dihydrate with increases in bioavailability up to nearly 10-fold. © 2011 American Chemical Society. Source

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