Leigh syndrome, a severe neurological disorder is commonly caused by homozygous or bi-allelic pathogenic variants in the SURF1 gene. SURF1 deficiency leads to dysfunction of Cytochrome C Oxidase (COX) activity, which is crucial for mitochondrial oxidative phosphorylation. Understanding COX activity's correlation with disease severity is essential for developing SURF1 Leigh Syndrome biomarkers. Thi...

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Epilepsy is a disease with diverse etiology; however, greater than 70%–80% of epileptic syndromes are thought to be associated with some genetic abnormality. Because of our fast-expanding genetic knowledge in epilepsy, we are approaching a new era of clinical management. We have an increased understanding of the underlying pathogenesis of genetic epilepsy as well as novel targets for precision the...

Recent advancements in gene supplementation therapy are expanding the options for the treatment of neurological disorders. Among the available delivery vehicles, adeno-associated virus (AAV) is often the favoured vector. However, the results have been variable, with some trials dramatically altering the course of disease whereas others have shown negligible efficacy or even unforeseen toxicity. Un...

SURF1 (surfeit locus protein 1)-related Leigh syndrome is an early-onset neurodegenerative disorder, characterized by reduction in complex IV activity, resulting in disrupted mitochondrial function. Currently, there are no treatment options available. To test our hypothesis that adeno-associated viral vector serotype 9 (AAV9)/human SURF1 (hSURF1) gene replacement therapy can provide a potentially ...

Cellular arachidonic acid (AA), an unsaturated fatty acid found ubiquitously in plasma membranes, is metabolized to different prostanoids, such as prostacyclin (PGI(2)) and prostaglandin E(2) (PGE(2)), by the three-step reactions coupling the upstream cyclooxygenase (COX) isoforms (COX-1 and COX-2) with the corresponding individual downstream synthases. While the vascular actions of these prostano...

Uncontrollable bleeding is still a worldwide killer. In this study, we aimed to investigate a novel approach to exhibit effective haemostatic properties, which could possibly save lives in various bleeding emergencies. According to the structure-based enzymatic design, we have engineered a novel single-chain hybrid enzyme complex (SCHEC), COX-1-10aa-TXAS. We linked the C-terminus of cyclooxygenase...

Addiction is characterized by compulsive drug seeking and taking behavior, which is thought to result from persistent neuroadaptations, encoded by changes of gene expression. We previously demonstrated that the changes in synaptic plasticity were required for the formation of aversive memories associated with morphine withdrawal. However, the proteins involved in synaptic plasticity and aversive m...

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Vascular prostanoids, isomerized from an intermediate prostaglandin (PG), H(2), produced by cyclooxygenase (COX), exert various effects on the vascular system, both protective and destructive. During endothelial dysfunction, vascular protector prostacyclin/prostaglandin I(2) (PGI(2)) is decreased, while inflammatory PGE(2) and thrombotic TXA(2) are increased. Therefore, our research aim was to rev...

An accurate and reliable UPLC-MS/MS method is reported for the quantification of endogenous Prostaglandin E2 (PGE(2)) in rat colonic mucosa and polyps. This method adopted the "surrogate analyte plus authentic bio-matrix" approach, using two different stable isotopic labeled analogs - PGE(2)-d9 as the surrogate analyte and PGE(2)-d4 as the internal standard. A quantitative standard curve was const...

Key residues and binding mechanisms of PGE(1) and PGE(2) on prostanoid receptors are poorly understood due to the lack of X-ray structures for the receptors. We constructed a human EP3 (hEP3) model through integrative homology modeling using the X-ray structure of the β(2)-adrenergic receptor transmembrane domain and NMR structures of the thromboxane A2 receptor extracellular loops. PGE(1) and PGE...

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The effect of aging on learning and memory has been intensively studied. However, the mechanisms underlying impairment of memory functions at middle age remains inexplicit. To address this question, we assessed the spatial working memory and long-term memory of middle-aged (16-18 months) rats with delayed alternation in T-maze and water maze task respectively. We observed a significant impairment ...

Aversive memories associated with drug withdrawal may contribute to persistent drug seeking. Molecular mechanisms that are critical for aversive memory formation have yet to be elucidated. Recently, we showed in a rat conditioned place aversion (CPA) model that synaptic actin polymerization in the amygdala were required for aversive memory information. Here, we demonstrated that actin polymerizati...