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Skoumalova A.,Charles University | Hort J.,Charles University | Hort J.,St Annes University Hospital Brno
Journal of Cellular and Molecular Medicine | Year: 2012

Alzheimer′s disease (AD) represents a highly common form of dementia, but can be diagnosed in the earlier stages before dementia onset. Early diagnosis is crucial for successful therapeutic intervention. The introduction of new diagnostic biomarkers for AD is aimed at detecting underlying brain pathology. These biomarkers reflect structural or biochemical changes related to AD. Examination of cerebrospinal fluid has many drawbacks; therefore, the search for sensitive and specific blood markers is ongoing. Investigation is mainly focused on upstream processes, among which oxidative stress in the brain is of particular interest. Products of oxidative stress may diffuse into the blood and evaluating them can contribute to diagnosis of AD. However, results of blood oxidative stress markers are not consistent among various studies, as documented in this review. To find a specific biochemical marker for AD, we should concentrate on specific metabolic products formed in the brain. Specific fluorescent intermediates of brain lipid peroxidation may represent such candidates as the composition of brain phospholipids is unique. They are small lipophilic molecules and can diffuse into the blood stream, where they can then be detected. We propose that these fluorescent products are potential candidates for blood biomarkers of AD. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. Source


Gora A.,Masaryk University | Brezovsky J.,Masaryk University | Damborsky J.,Masaryk University | Damborsky J.,St Annes University Hospital Brno
Chemical Reviews | Year: 2013

The dynamic motion of enzymes during catalytic events is one of the many aspects of protein chemistry that are currently insufficiently well understood. On one hand, proteins need to have well-defined and organized structures in order to maintain stable functionality in the intracellular environment. On the other hand, some degree of flexibility is often required for catalytic activity. Molecular dynamics simulations have provided key insights into the importance of protein dynamics in catalysis, such as the observation of substrate access and product exit pathways that cannot be identified by inspecting crystal structures. Spatial localization of the hydrophobic and hydrophilic regions within the structure of a protein is important in maintaining its proper fold and can also be crucial for catalytic function. The various steps of an enzymatic reaction may require different environments. Source


Marini V.,Masaryk University | Krejci L.,Masaryk University | Krejci L.,St Annes University Hospital Brno
DNA Repair | Year: 2012

The budding yeast Srs2 protein possesses 3' to 5' DNA helicase activity and channels untimely recombination to post-replication repair by removing Rad51 from ssDNA. However, it also promotes recombination via a synthesis-dependent strand-annealing pathway (SDSA). Furthermore, at the replication fork, Srs2 is required for fork progression and prevents the instability of trinucleotide repeats. To better understand the multiple roles of the Srs2 helicase during these processes, we analysed the ability of Srs2 to bind and unwind various DNA substrates that mimic structures present during DNA replication and recombination. While leading or lagging strands were efficiently unwound, the presence of ssDNA binding protein RPA presented an obstacle for Srs2 translocation. We also tested the preferred directionality of unwinding of various substrates and studied the effect of Rad51 and Mre11 proteins on Srs2 helicase activity. These biochemical results help us understand the possible role of Srs2 in the processing of stalled or blocked replication forks as a part of post-replication repair as well as homologous recombination (HR). © 2012 Elsevier B.V. Source


Hahn E.A.,Brandeis University | Wang H.-X.,University of Stockholm | Andel R.,University of South Florida | Andel R.,St Annes University Hospital Brno | Fratiglioni L.,University of Stockholm
American Journal of Geriatric Psychiatry | Year: 2014

Objective Sleep problems may adversely affect neuronal health. We examined a subjective report of change (reduced duration and/or depth) in sleep pattern in relation to subsequent risk of incident all-cause dementia and Alzheimer disease (AD) over 9 years. Methods This longitudinal study used data from a population-based sample of 214 Swedish adults aged 75 and over who were dementia-free both at baseline and at first follow-up (3 years later). The sample was 80% female and, on average, 83.4 years of age at baseline. All participants underwent a thorough clinical examination to ascertain all-cause dementia and AD. Results Forty percent of participants reported a change in sleep duration at baseline. Between the 6th and 9th year after baseline, 28.5% were diagnosed with all-cause dementia, 22.0% of whom had AD. Reduced sleep was associated with a 75% increased all-cause dementia risk (hazard ratio: 1.75; 95% confidence interval: 1.04-2.93; Wald = 4.55, df = 1, p = 0.035) and double the risk of AD (hazard ratio: 2.01; 95% confidence interval: 1.12-3.61; Wald = 5.47, df = 1, p = 0.019) after adjusting for age, gender, and education. The results remained after adjusting for lifestyle and vascular factors but not after adjusting for depressive symptoms. No evidence supported a moderating effect of the use of sleeping pills, and the sleep-dementia relationship remained after controlling for the presence of the apolipoprotein E ε4 allele. Conclusion Self-reported sleep problems may increase the risk for dementia, and depressive symptoms may explain this relationship. Future research should determine whether treatment, in particular, behavioral or nonpharmacologic treatment, may represent one avenue toward reduction of dementia risk in late life. © 2014 American Association for Geriatric Psychiatry. Source


Giannopoulos S.,Columbia University | Giannopoulos S.,University of Ioannina | Katsanos A.H.,University of Ioannina | Tsivgoulis G.,Democritus University of Thrace | And 2 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2012

HMG-CoA reductase inhibitors (statins) are associated with improved stroke outcome. This observation has been attributed in part to the palliative effect of statins on cerebral hemodynamics and cerebral autoregulation (CA), which are mediated mainly through the upregulation of endothelium nitric oxide synthase (eNOS). Several animal studies indicate that statin pretreatment enhances cerebral blood flow after ischemic stroke, although this finding is not further supported in clinical settings. Cerebral vasomotor reactivity, however, is significantly improved after long-term statin administration in most patients with severe small vessel disease, aneurysmal subarachnoid hemorrhage, or impaired baseline CA. © 2012 ISCBFM All rights reserved. Source

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