O-GlcNAc – a posttranslational modification implicated in Alzheimer disease?

O-linked N-acetylglucosamine (O-GlcNAc) is a highly dynamic posttranslational modification which has been found on a myriad of nucleocytoplasmic proteins. O-GlcNAc addition and removal are catalyzed by two conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA). Alzheimer disease (AD) is one of the most common forms of dementia. The histopathological hallmarks of AD brain include neurofibrillary tangles of hyperphosphorylated tau and senile plaques consisting mainly of aggregated amyloid β-peptides which are generated from a larger transmembrane protein, the amyloid precursor protein (APP). O-GlcNAc has been extensively studied in the context of AD. However, contradicting results have demonstrated either increased or decreased O-GlcNAcylation in AD brain. To date the underlying cause(s) as well as potential consequences of altered O-GlcNAcylation in AD are unknown. Both the microtubule-associated protein tau and APP are O-GlcNAc-modified. While some studies show that increased O-GlcNAcylation reduces tau hyperphosphorylation, the function of the O-GlcNAc modification of APP is not yet understood. In this work, the potential involvement of O-GlcNAc in different aspects of AD pathology was investigated. For this purpose, a recently established in vitro OGT assay was used to demonstrate the O-GlcNAcylation of cyclin-dependent kinase 5 (cdk5), a kinase that phosphorylates both APP and tau and has been implicated in AD pathogenesis. The functional role of O-GlcNAcylation of cdk5 remains to be elucidated. Since OGT assays are useful tools for the analysis of OGT activity or for the identification of novel OGT targets, the established in vitro OGT assay was further refined using the nuclear pore protein Nup62 as a model substrate. To investigate the (potential) role of APP´s O-GlcNAcylation, effects of O-GlcNAc modulation on the proteolytic processing of APP were analyzed in cell culture studies. Increased O-GlcNAc expression by OGA inhibition did, however, not alter levels of the APP cleavage products sAPPα and sAPPβ. Furthermore, O-GlcNAc and, for the first time, O-GlcNAc cycling enzymes were investigated in brain samples of subjects with AD and amnestic mild cognitive impairment (MCI), a prodromal stage of AD. In AD brains, increased O-GlcNAcylation correlated with reduced OGA expression and activity while OGT expression was unaltered when compared with age-matched controls. In MCI brains, no changes in O-GlcNAc, OGA or OGT expression were observed. Taken together this work suggests that O-GlcNAc may not play a direct role in APP processing and that altered O-GlcNAcylation may be a late event in the progression of AD. In combination with recent reports demonstrating positive effects of OGA inhibition in animal models of AD, it is obvious that further studies are needed to elucidate the role of O-GlcNAc in AD

Development and Evaluation of an Impedance Cardiographic System to Measure Cardiac Output and Other Cardiac Parameters, 1 July 1968 - 30 June 1969

Impedance cardiographic system to measure cardiac output and cardiovascular function

In Vitro Antioxidant and Free Radical Scavenging activities of Various Solvent Extracts of Marsdenia Brunoniana

The various solvent extracts of Marsdenia brunoniana was prepared and evaluated for its in vitro antioxidant, free radical scavenging and in vitro alpha glucosidaseand alpha amylase inhibitory activities. Amongst the various solvent extracts of M.brunoniana, ethanol extract shows more pronounced activity while comparing with remaining solvent extracts. Hence, the ethanolic extract of Marsdenia brunoniana has been studied for the toxicological, antidiabetic, antihyperlipidemic and nephroprotective activities in STZ-NAA induced diabetic animals. And the acute toxicity results revealed that the extract did not produce any motility to toxic effects even at maximum dose administered. Subacute toxicity study also explored the non-toxic nature of the extract. Further, the extract was subjected to various studies like glucose uptake assay, DNA protection assay and in vitro cytotoxic assay. The results obtained in these studies revealed that the extract is significantly increases the glucose uptake and it protects the DNA and it also did not produce any cytotoxic activity at the tested dose levels. The Preliminary phytochemical analysis, HPLC, HPTLC and GC-MS analysis of EEMB also revealed the presence of many phytochemical compounds such as flavonoids, phenols, methyl-α-D-Glucopyranoside, 4-C-methyl-Myo-Inositol, n-hexadecanoic acid, phytol, rutin, quercetin, ferulic acid, caffeic acid, gallic acid and which are having pronounced biological effects. The EEMB significantly reduces the elevated level of glucose in blood and level of lipid profile in diabetic persuaded animals. At the same time it is able to increase the insulin secretion, restore the antioxidant enzyme system and prevent the weight loss in diabetic animals. It also has the incredible effect on reducing the glycosylated hemoglobin level in diabetic induced animals

An approach to the physiology of appetite.

A thesis presented for the degree of Master of Science.WHSLYP201

Effects of administration of Hibiscus sabdariffa aqueous calyx extracts on neonatal programming of metabolic dysfunction

Hibiscus sabdariffa (HS) is a plant of the Malvaceae family that has anti-obesity, antihypertensive, hypocholesterolaemic, anti-oxidant and anti-cancer properties. Dietary manipulations during the suckling period cause precocious maturation of the gastrointestinal tract (GIT). Events in early life affect the individual‘s metabolic health in later life. This study investigated the effects of early administration of the aqueous calyx extracts of HS on the growth performance, general health and the GIT of neonatal rats and whether it conferred protection or predisposition to the development of metabolic dysfunction in adolescence. The study was carried out in two phases. The first phase was to determine the effects of HS aqueous calyx extracts on the growth performance, metabolic substrates and the development of the neonatal rat GIT. In the second phase, the effects of the early administration of the HSE on the response of the pups to diet induced metabolic dysfunction were investigated. In phase one, forty two 4-day old Sprague Dawley pups of both sexes were randomly assigned to three treatment groups. Each group consisted of 7 males and 7 females. The control group received distilled water at 10ml.kg-1 b.w while the other two groups received either a low (50mg.kg-1) or high dose (500mg.kg-1) of the HS aqueous calyx extracts via oral gavage daily for 9 consecutive days. The rats were euthanased and their tissues harvested and analyzed. Pups that were administered with the high dose HSE had significantly heavier small intestines relative to the body mass when compared to those on the low dose HSE (P<0.01) and the control group (p<0.001). Pups in the high dose HSE group had significantly heavier caeca (p<0.05) than those in the low dose HSE group. In the second phase, eighty five 4-day old Sprague Dawley rat pups were used. They were initially divided randomly into three groups and received similar treatments as in phase one up to postnatal day (PND) 14. There was no intervention from PND14 to PND 21 when the pups were weaned. The rats in each of the treatment groups were further divided into a control group that continued on their normal rat chow diet and a test group that received high fructose (20% w/v) in their drinking water for 30 days in order to induce metabolic dysfunction. Each of the six study groups had at least 5 male and 5 female rats. The male rats in each of the treatment groups gained more body mass than their corresponding female counterparts in the control and treatment groups (p<0.001). Female rats that received high dose HSE in the neonatal period had significantly greater visceral fat pad (p≤0.05) than the males in the groups. There were no negative effects on the rats‘ general health. At the end of the study, features of metabolic syndrome did not manifest in the control or any of the treatment groups. Hibiscus sabdariffa aqueous calyx extracts did not exhibit any long term effects and therefore may be considered safe for consumption in the neonatal age group