A5014159327- Adipose Tissue and Metabolism
- Pancreatic function and diabetes
- Diabetes Management and Research
- Diabetes and associated disorders
- Diet and metabolism studies
- Regulation of Appetite and Obesity
- Metabolism, Diabetes, and Cancer
- Adipokines, Inflammation, and Metabolic Diseases
- Genomics, phytochemicals, and oxidative stress
- Diabetes Management and Education
- Glycosylation and Glycoproteins Research
- Galectins and Cancer Biology
- Signaling Pathways in Disease
- Calpain Protease Function and Regulation
- Diet, Metabolism, and Disease
- Hormonal Regulation and Hypertension
- Liver Disease Diagnosis and Treatment
- Alzheimer's disease research and treatments
- Aldose Reductase and Taurine
- Lysosomal Storage Disorders Research
- Advanced Glycation End Products research
- Microbial Inactivation Methods
- Pharmacogenetics and Drug Metabolism
- Stress Responses and Cortisol
- Glutathione Transferases and Polymorphisms
University of Dundee
2016-2025
Ninewells Hospital
2014-2024
General University Hospital in Prague
2023
Charles University
2023
University of Ulster
2016
University of Helsinki
2016
MRC Protein Phosphorylation and Ubiquitylation Unit
2016
University of Glasgow
2016
University of Edinburgh
2010
The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood.Here, we have studied anti-inflammatory effects of and their relationship to antihyperglycemic properties.In primary hepatocytes from healthy animals, IKKβ (inhibitor kappa B kinase) inhibitor BI605906 both inhibited tumor necrosis factor-α-dependent IκB degradation expression proinflammatory mediators interleukin-6,...
Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes early risk factors AD (Alzheimer's disease). An essential feature pathology is the presence BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production toxic peptides. However, whether also plays a role in presently unknown. We have used transgenic mice to analyse effects loss on body weight, lipid homoeostasis. BACE1-/- lean, with decreased adiposity, higher energy...
Accumulation of reactive oxygen species (i.e., oxidative stress) is a leading cause beta cell dysfunction and apoptosis in diabetes. NRF2 (NF-E2 p45-related factor-2) regulates the adaptation to stress, its activity negatively regulated by redox-sensitive CUL3 (cullin-3) ubiquitin ligase substrate adaptor KEAP1 (Kelch-like ECH-associated protein-1). Additionally, repressed insulin-regulated Glycogen Synthase Kinase-3 (GSK3). We have demonstrated that phosphorylation GSK3 enhances β-TrCP...
Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis is associated with increased concentrations bile acids. We investigated whether this was mediated through acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism 5beta-reductase.
Diabetes, obesity, and Alzheimer’s disease (AD) are associated with vascular complications impaired nitric oxide (NO) production. Furthermore, increased β-site amyloid precursor protein–cleaving (APP-cleaving) enzyme 1 (BACE1), APP, β-amyloid (Aβ) linked development BACE1 Aβ accompany hyperglycemia hyperlipidemia. However, the causal relationship between obesity diabetes, Aβ, dysfunction is unclear. We report that diet-induced (DIO) in mice plasma Aβ42 correlated decreased NO...
O-GlcNAcylation is an essential post-translational modification that has been implicated in neurodevelopmental and neurodegenerative disorders. O-GlcNAcase (OGA), the sole enzyme catalyzing removal of O-GlcNAc from proteins, emerged as a potential drug target. OGA consists N-terminal catalytic domain C-terminal pseudo histone acetyltransferase (HAT) with unknown function. To investigate phenotypes specific to loss activity dissect role HAT domain, we generated constitutive knock-in mouse...
ABSTRACT The addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins (referred as O-GlcNAcylation) is a modification that crucial for vertebrate development. O-GlcNAcylation catalyzed by O-GlcNAc transferase (OGT) and reversed O-GlcNAcase (OGA). Missense variants OGT have recently been shown segregate with an X-linked syndromic form intellectual disability, OGT-linked congenital disorder glycosylation (OGT-CDG). Although the existence OGT-CDG suggests neurodevelopment and/or...
It remains uncertain whether recurrent nonsevere hypoglycemia (Hypo) results in long-term cognitive impairment type 1 diabetes (T1D). This study tested the hypothesis that specifically T1D state, Hypo leads to via a pathological response oxidative stress. Wild-type (Control) and nuclear factor–erythroid 2 p45–related factor (Nrf2) null mice were studied. Eight groups of (Control Nrf2−/− ± Hypo) subject recurrent, twice-weekly, insulin or saline injections over 4 weeks, after which function...
Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents should promote weight normalisation improve glucose homeostasis. protease Bace1 drives beta amyloid (Aβ) production obesity elevating hypothalamic activity Aβ1-42 production. Pharmacological inhibition of reduces body weight, improves homeostasis lowers plasma in diet-induced obese (DIO) mice....
In patients with stable coronary artery disease, plasma levels of 7-ketocholesterol (7-KC), found at high in atherosclerotic lesions, predict risk incident heart failure dose dependently, potentially contributing to disease aetiology. Previous studies demonstrated that 7-KC can elicit effects on macrophage function; however, the proteome have not been studied systematically. Here we used quantitative mass spectrometry establish effect mouse proteome. independently mediated dynamic changes,...
In diabetes, chronic hyperglycaemia leads to cognitive impairment, neurodegeneration and dementia. a rodent model of streptozotocin (STZ)-induced type 1 diabetes (STZ-T1D), we previously demonstrated that recurrent hypoglycaemia (RH) further exacerbates this process through mechanism involving increased oxidative inflammatory stress overwhelms the compensatory activation nuclear factor erythroid 2-related 2 (Nrf2) antioxidant system, which was insufficient prevent impairment. The current...
ABSTRACT Aims The benefit of salicylate in the treatment diabetes has been recognized for over a century; however, challenging side effects have prevented widespread use. A better understanding relevant enzyme targets mediating its anti‐hyperglycaemic effect may lead to development novel therapies diabetes. Here, we investigated contribution 5′‐adenosine monophosphate ( AMP )‐dependent inhibition fructose‐1,6‐bisphosphatase 1 FBP1 ) action salicylate. Methods We studied ‐insensitive G27P...
CYP2S1 is an extrahepatic cytochrome P450 (P450) that shows marked individuality in constitutive and inducible expression. mRNA expression increased psoriasis by treatments for psoriasis, including retinoids UV radiation, although endogenous substrates remain poorly characterized. Because previous model systems have overexpressed modified bacteria, human HaCaT keratinocyte cells were screened regulatable activity compared with a novel Chinese hamster ovary (CHO)-based cell line engineered to...
Lithium has been used for decades to treat Bipolar Disorder. Some of its therapeutic benefits may be through inhibition Glycogen Synthase Kinase (GSK)-3. Enhanced GSK3 activity associates with development Alzheimer's disease (AD), therefore lithium is a currently potential repurposed prevention Dementia. An important step towards clinical trial AD using establish the dose that blocks in Mild Cognitive Impairment (MCI), high-risk condition progression AD. We investigated volunteer...
O-GlcNAcylation is an abundant post-translational modification in the nervous system, linked to both neurodevelopmental and neurodegenerative disease. However, mechanistic links between these phenotypes site-specific remain largely unexplored. Here, we show that Ser517 of microtubule-binding protein Collapsin Response Mediator Protein-2 (CRMP2) increases with age. By generating characterizing a Crmp2S517A knock-in mouse model, demonstrate loss leads small decrease body weight mild memory...
Central to the development of diabetic macro- and microvascular disease is endothelial dysfunction, which appears well before any clinical sign but, importantly, potentially reversible. We previously demonstrated that hyperglycemia activates nuclear factor activated T cells (NFAT) in conduit medium-sized resistance arteries NFAT blockade abolishes diabetes-driven aggravation atherosclerosis. In this study, we test whether plays a role dysfunction diabetes. NFAT-dependent transcriptional...
Hypoglycemia is a major adverse effect of insulin therapy for people with type 1 diabetes (T1D). Profound defects in the normal counterregulatory response to hypoglycemia explain frequency occurrence T1D. Defective counterregulation results large extent from prior exposure per se, leading condition called impaired awareness (IAH), cause which unknown. In current study, we investigate hypothesis that IAH develops through special adaptive memory referred as habituation. To test this...
Abstract Aims/hypothesis Chronic hyperglycaemia and recurrent hypoglycaemia are independently associated with accelerated cognitive decline in type 1 diabetes. Recurrent rodent models of chemically induced (streptozotocin [STZ]) diabetes leads to impairment memory-related tasks hippocampal oxidative damage. This study examined the hypothesis that post-hypoglycaemic STZ-diabetes exacerbates stress explored potential contributory mechanisms. Methods The hyperinsulinaemic glucose clamp...