Publications by authors named "Lee Stanyer"
Mesial temporal lobe epilepsy with hippocampal sclerosis represents the most common epilepsy syndrome in adult patients with medically intractable partial epilepsy. Mesial temporal lobe epilepsy is usually regarded as a polygenic and complex disorder, still poorly understood but probably caused and perpetuated by dysregulation of numerous biological networks and cellular functions. The study of gene expression changes by single nucleotide polymorphisms in regulatory elements (expression quantitative trait loci, eQTLs) has been shown to be a powerful complementary approach to the detection and understanding of risk loci by genome-wide association studies.
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- Nrf2, a transcription factor, and its repressor Keap1 control a significant network of protective genes, primarily influencing drug metabolism and antioxidants.
- Research shows that Nrf2 plays a crucial role in regulating mitochondrial function in mouse neurons and fibroblasts; its loss causes reduced ATP levels and impaired energy production.
- Activation of Nrf2 improves mitochondrial potential and efficiency, demonstrating that it directly influences energy metabolism, crucial for cellular protection.
The accumulation of oxidatively modified proteins has been shown to be a characteristic feature of many neurodegenerative disorders and its regulation requires efficient proteolytic processing. One component of the mitochondrial proteolytic system is Lon, an ATP-dependent protease that has been shown to degrade oxidatively modified aconitase in vitro and may thus play a role in defending against the accumulation of oxidized matrix proteins in mitochondria. Using an assay system that allowed us to distinguish between basal and ATP-stimulated Lon protease activity, we have shown in isolated non-synaptic rat brain mitochondria that Lon protease is highly susceptible to oxidative inactivation by peroxynitrite (ONOO(-)).
View Article and Find Full Text PDFParkinson's disease (PD) is a common age-related neurodegenerative disease and it is critical to develop models which recapitulate the pathogenic process including the effect of the ageing process. Although the pathogenesis of sporadic PD is unknown, the identification of the mendelian genetic factor PINK1 has provided new mechanistic insights. In order to investigate the role of PINK1 in Parkinson's disease, we studied PINK1 loss of function in human and primary mouse neurons.
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- The study explores how high levels of LDL (low-density lipoprotein), especially when oxidized, affect blood vessel responses to beta-amyloid (Abeta) in a context relevant to aging and Alzheimer's disease (AD).
- It was found that soluble forms of Abeta (specifically Abeta40 and Abeta42) combined with oxidized LDL led to increased constriction of blood vessels and decreased relaxation responses, showing a potential link between cholesterol levels and vascular issues in AD.
- This indicates that managing hypercholesterolemia could be a crucial factor in addressing cerebrovascular problems associated with Alzheimer's, highlighting new pathways for potential treatments.
Article Synopsis
- The study investigates how different forms of the beta-amyloid peptide (Abeta) affect platelet function, specifically looking at soluble vs. fibrillar states of Abeta(1-40).
- Soluble Abeta(1-40) showed a minor enhancement in platelet aggregation and serotonin release only at high concentrations, while fibrillar Abeta(1-40) significantly increased both responses as its concentration rose.
- The presence of plasma lipoproteins affected the potency of Abeta fibrils, leading to less effective platelet responses compared to pure homogeneous Abeta fibrils, suggesting lipoproteins can interfere with Abeta's interaction with platelets.
Article Synopsis
- At low concentrations (1 microM), soluble beta-amyloid (A beta 40) was found to reduce the ability of noradrenaline (NA) to cause contractions in rat aortic rings, particularly in SD rats, leading to a significant increase in NA's effectiveness (EC(50) values).
- In contrast, at higher concentrations (5 microM), A beta 40 actually enhanced NA-induced constriction and decreased the effectiveness of NA, suggesting a dose-dependent effect on vascular responses.
- The study proposes that low levels of A beta 40 might enhance the production of endothelial vasodilators, while higher concentrations could create toxic oligomers that impair vasodilator function, leading to increased vasoconstriction
A N-derivatized 3-dimethylaminopropyloxypyrazole library was prepared using solution-phase parallel synthesis. The library was designed using physicochemical constraints designed to remove non-membrane-permeable molecules. Cupric acetate-mediated N-arylation with aryl boronic acids proceeded regioselectively to form the N-2-substituted derivatives.
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- Alzheimer's disease (AD) involves the buildup of beta-amyloid (A beta) fibrils in the brain, and understanding factors influencing this process can lead to new treatments.
- Low-density lipoprotein (LDL), particularly in its oxidised form, promotes A beta fibrillogenesis, which depends on the concentration and oxidative state of LDL.
- The effects of LDL on A beta are significant, enhancing vascular responses and potentially indicating that modifying plasma lipoproteins with statins or antioxidants could provide therapeutic advantages in AD management.
Evaluation of methods for the extraction of nitrite and nitrate in biological fluids employing high-performance anion-exchange liquid chromatography for their determination.
J Chromatogr B Analyt Technol Biomed Life Sci
November 2002
Measurements of nitrite (NO(2)(-)) and nitrate (NO(3)(-)) in biological fluids are proposed as indices of cellular nitric oxide (NO) production. Determination of NO(2)(-) and NO(3)(-) in standard solutions is not difficult, however, determinations which reflect accurately cellular NO synthesis represent a considerable analytical challenge. Problems are often encountered arising from background NO(2)(-)/NO(3)(-) contamination in experimental solutions and laboratory hardware, and with methods for sample extraction.
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- The beta-amyloid peptide's toxicity in Alzheimer's disease is linked to how it polymers, with oxidized plasma lipoproteins significantly increasing this polymerization.
- The study explored the effects of various treatments, finding that common antioxidants like ascorbic acid and trolox did not prevent Abeta fibrillogenesis, but aminoguanidine showed promise as an antioxidant in inhibiting polymerization.
- Additionally, the presence of apoprotein components in lipoproteins is crucial for enhancing Abeta polymerization, suggesting their involvement in the interaction with aldehydes.