Increased 5-Lipoxygenase Immunoreactivity in the Hippocampus of Patients With Alzheimer's Disease

The proinflammatory enzyme 5-lipoxygenase (5-LOX) is upregulated in Alzheimer''s disease (AD), but its localization and association with the hallmark lesions of the disease, β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs), is unknown. This study examined the distribution and cellular localization of 5-LOX in the medial temporal lobe from AD and control subjects. The spatial relationship between 5-LOX immunoreactive structures and AD lesions was also examined. We report that, in AD subjects, 5-LOX immunoreactivity is elevated relative to controls, and its localization is dependent on the antibody-targeted portion of the 5-LOX amino acid sequence. Carboxy terminus–directed antibodies detected 5-LOX in glial cells and neurons, but less frequently in neurons with dystrophic (NFT) morphology. In contrast, immunoreactivity observed using 5-LOX amino terminus–directed antibodies was virtually absent in neurons and abundant in NFTs, neuritic plaques, and glia. Double-labeling studies showed a close association of 5-LOX–immunoreactive processes and glial cells with Aβ immunoreactive plaques and vasculature and also detected 5-LOX in tau immunoreactive and amyloid containing NFTs. Different immunolabeling patterns with antibodies against carboxy vs amino terminus of 5-LOX may be caused by post-translational modifications of 5-LOX protein in Aβ plaques and NFTs. The relationship between elevated intracellular 5-LOX and hallmark AD pathological lesions provides further evidence that neuroinflammatory pathways contribute to the pathogenesis of AD. (J Histochem Cytochem 56:1065–1073, 2008)     

Affective pictures processing is reflected by an increased long-distance EEG connectivity

Analysis of affective picture processing by means of EEG has invaded the literature. The methodology of event-related EEG coherence is one of the essential methods used to analyze functional connectivity. The aims of the present study are to find out the long range EEG connectivity changes in perception of different affective pictures and analyze gender differences in these long range connected networks. EEGs of 28 healthy subjects (14 female) were recorded at 32 locations. The participants passively viewed emotional pictures (IAPS, unpleasant, pleasant, neutral). The long-distance intra-hemispheric event-related coherence was analyzed for delta (1–3.5 Hz), theta (4–7.5 Hz), and alpha (8–13 Hz) frequency ranges for F₃–T₇, F₄–T₈, F₃–TP₇, F₄–TP₈, F₃–P₃, F₄–P₄, F₃–O₁, F₄–O₂, C₃–O₁, C₄–O₂ electrode pairs. Unpleasant pictures elicited significantly higher delta coherence values than neutral pictures (p < 0.05), over fronto-parietal, fronto-occipital, and centro-occipital electrode pairs. Furthermore, unpleasant pictures elicited higher theta coherence values than pleasant (p < 0.05) and neutral pictures (p < 0.05). The present study showed that female subjects had higher delta (p < 0.05) and theta (p < 0.05) coherence values than male subjects. This difference was observed more for emotional pictures than for neutral pictures. This study showed that the brain connectivity was higher during emotional pictures than neutral pictures. Females had higher connectivity between different parts of the brain than males during emotional processes. According to these results, we may comment that increased valence and arousal caused increased brain activity. It seems that not just single sources but functional networks were also activated during perception of emotional pictures.     

Glucocorticoids Stimulate Inflammatory 5-Lipoxygenase Gene Expression and Protein Translocation in the Brain

In the brain, the expression of 5-lipoxygenase (5-LO), the enzyme responsible for the synthesis of inflammatory leukotrienes, increases during aging. Antiinflammatory drugs are currently being evaluated for the treatment of aging-associated neurodegenerative diseases such as Alzheimer's disease. Although generally considered antiinflammatory, glucocorticoids, whose production also increases during aging, are not particularly effective in this disease. In human monocytes, 5-LO mRNA content increases on exposure to the synthetic glucocorticoid dexamethasone, which prompted us to hypothesize that glucocorticoids might increase 5-LO expression in the brain as well. We treated rats for 10 days either with corticosterone (implanted subcutaneously) or with dexamethasone (injected daily); they were killed on day 10 after pellet implantation or 24 h after the 10th dexamethasone injection. We found increased levels of 5-LO mRNA and protein in hippocampus and cerebellum of glucocorticoid-treated rats; 5-LO-activating protein (FLAP) mRNA content was not affected. Using western immunobloting, we also observed the concurrent translocation of 5-LO protein from cytosol to membrane, an indication of its activation. Thus, glucocorticoid-mediated up-regulation of the neuronal 5-LO pathway may contribute to rendering an aging brain vulnerable to degeneration.     

Alkaloids of Fumaria vaillantii

The aerial parts of Turkish Fumaria vaillantii yielded 26 isoquinoline alkaloids. Of these, oxysanguinarine, (±)-8-acetonyldihydrosanguinarine, (±)-8-methoxydihydrosanguinarine and fumaramidine are reported for the first time from this plant. New alkaloids for the genus Fumaria are dihydrosanguinarine, norsanguinarine, (+)-isocorydine, (?)-corledine and (+)-juziphine. This is the first occurrence of the isoquinolone N-methylcorydaldine in a member of the Fumariaceae. Spectral data are given for the new compound, E-fumaramine.     

Association of cholesteryl ester transfer protein −629C > A polymorphism with high‐density lipoprotein cholesterol levels in coronary artery disease patients

In Turkish population, plasma HDL‐C levels were found to be lower than in any other country and it is suggested that this is associated with genetic origin. The cholesteryl ester transfer protein (CETP) ?629C > A polymorphism is associated with lower plasma CETP concentration, with increased HDL‐C level. In the present study, the frequency of ?629C > A polymorphism in patients with coronary artery disease (CAD) was investigated and the effect of genotype on HDL‐C was evaluated in a Turkish population. For this aim CETP ?629C > A polymorphism was studied in angiographically documented CAD patients and healthy controls. There was no statistical significance in the distribution of genotypes between patients and controls. Although A allele carriers with CAD had significantly lower HDL‐C levels than controls, plasma lipid levels showed no difference according to the genotypes. Adjustment by a logistic regression model predicting CAD status through HDL‐C and including some risk factors as covariate indicated that the HDL‐C doesn't have a significant association with CAD risk in CA and AA genotype carriers. Smoking, gender and hypertension were the common predictors for the HDL‐C levels in CA and AA carriers. Although HDL‐C appeared to be the only significant predictor of CAD in our study groups, the contribution of CETP ?629C > A polymorphism to the alterations in HDL‐C level appears to be weak to mention a protective effect of this polymorphism for CAD. In conclusion, the findings of the present study indicate that the CETP ?629C > A polymorphism is not among the determinants of the coronary artery disease in Turks. Copyright © 2009 John Wiley & Sons, Ltd.     

Increased Hippocampal 5-Lipoxygenase mRNA Content in Melatonin-Deficient, Pinealectomized Rats

Abstract: Tryptophan hydroxylase, the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin, is activated by protein kinase A and calcium/calmodulin-dependent protein kinase. One important aspect of the regulation of any enzyme by a phosphorylation-dephosphorylation cascade, and one that is lacking for tryptophan hydroxylase, lies in the identification of its site of phosphorylation by protein kinases. Recombinant forms of brain tryptophan hydroxylase were expressed as glutathione S -transferase fusion proteins and exposed to protein kinase A. This protein kinase phosphorylates and activates full-length tryptophan hydroxylase. The inactive regulatory domain of the enzyme (corresponding to amino acids 1–98) was also phosphorylated by protein kinase A. The catalytic core of the hydroxylase (amino acids 99–444), which expresses high levels of enzyme activity, was neither phosphorylated nor activated by protein kinase A. Conversion of serine-58 to arginine resulted in the expression of a full-length tryptophan hydroxylase mutant that, although remaining catalytically active, was neither phosphorylated nor activated by protein kinase A. These results indicate that the activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme.