A5018561796- Hormonal Regulation and Hypertension
- Stress Responses and Cortisol
- Tryptophan and brain disorders
- Apelin-related biomedical research
- Bipolar Disorder and Treatment
- Liver Disease Diagnosis and Treatment
- Enzyme Structure and Function
- Biochemical and Molecular Research
- Endometriosis Research and Treatment
- Biotin and Related Studies
- Reproductive System and Pregnancy
- Computational Drug Discovery Methods
- Metabolomics and Mass Spectrometry Studies
- Pharmacological Effects of Natural Compounds
- Receptor Mechanisms and Signaling
- Estrogen and related hormone effects
- Eicosanoids and Hypertension Pharmacology
- Adrenal Hormones and Disorders
- Porphyrin Metabolism and Disorders
- Adrenal and Paraganglionic Tumors
- Gut microbiota and health
- Adolescent and Pediatric Healthcare
- Diet and metabolism studies
- Amino Acid Enzymes and Metabolism
- Vitamin D Research Studies
University of Edinburgh
2014-2025
The Queen's Medical Research Institute
2014-2025
MRC Centre for Reproductive Health
2024
Centre for Inflammation Research
2024
MRC Centre for Regenerative Medicine
2024
Edinburgh College
2023
Maidstone and Tunbridge Wells NHS Trust
2021
Institute of Electrical and Electronics Engineers
2021
Gorgias Press (United States)
2021
Stevens Institute of Technology
2021
Aim: The present investigation was designed to determine the in vivo antidiabetic effect of naringenin (NG) normoglycaemic and diabetic rat models through blood glucose (GLU) measurements following acute subchronic time periods. Possible modes action NG were investigated its toxicity determined. Methods: Normoglycaemic non‐insulin‐dependent diabetes mellitus (NIDDM) treated for (5 days) periods with 50 mg/kg/day NG. Blood biochemical profiles determined after 5 days treatment NIDDM rats...
Steroid concentrations within tissues are modulated by intracellular enzymes. Such "steroid intracrinology" influences hormone-dependent cancers and obesity provides targets for pharmacological inhibition. However, no high resolution methods exist to quantify steroids target tissues. We developed mass spectrometry imaging (MSI), combining matrix assisted laser desorption ionization with on-tissue derivatization Girard T Fourier transform ion cyclotron resonance spectrometry, substrate...
8-Amino-7-oxononanoate synthase (also known as 7-keto-8-aminopelargonate synthase, EC 2.3.1.47) is a pyridoxal 5'-phosphate-dependent enzyme which catalyzes the decarboxylative condensation of l-alanine with pimeloyl-CoA in stereospecific manner to form 8(S)-amino-7-oxononanoate. This first committed step biotin biosynthesis. The mechanism Escherichia coli AONS has been investigated by spectroscopic, kinetic, and crystallographic techniques. X-ray structure holoenzyme refined at resolution...
Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of involved cancer. Phenotypic against MCF7 mammary adenocarcinoma cells generated target-agnostic structure-activity relationships biased subsequent designs breast cancer...
Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that product 3-hydroxykynurenine primes innate immune signaling to exacerbate during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma levels prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes...
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoids (GCs) from intrinsically inert 11-keto substrates inside cells, including neurons, thus amplifying steroid action. Excess GC action exerts deleterious effects on the hippocampus and causes impaired spatial memory, a key feature of age-related cognitive dysfunction. Mice with complete deficiency 11β-HSD1 are protected memory impairments aging. Here, we tested whether lifelong or short-term decreases in...
Chronic exposure to elevated levels of glucocorticoids has been linked age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short-term treatment aged, cognitively impaired C57BL/6 mice with potent selective 11β-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration central nervous system alone. Tg2576...
Reducing glucocorticoid exposure in the brain via intracellular inhibition of cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has emerged as a therapeutic strategy to treat cognitive impairment early Alzheimer's disease (AD). We sought discover novel, brain-penetrant 11β-HSD1 inhibitors potential medicines for treatment AD.Medicinal chemistry optimization series amido-thiophene analogues was performed identify potent and selective with optimized oral...
Acute kidney injury (AKI) following ischemia-reperfusion (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking kynurenine 3-monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. We show KMO is highly expressed in the exerts major metabolic control over biologically active metabolites 3-hydroxykynurenine, kynurenic acid, downstream metabolites. In experimental induced by IRI, Kmonull had preserved function, reduced tubular...
Abstract The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. parasite enters blood via bite tsetse fly where it wholly reliant on glycolysis for production ATP. Glycolytic enzymes have been regarded challenging drug targets because their highly conserved active sites and phosphorylated substrates. We describe development novel small molecule allosteric inhibitors trypanosome phosphofructokinase (PFK) that block...
Abstract Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington’s and Alzheimer’s. Most recently it been identified target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); devastating inflammatory condition with mortality rate excess 20%. Here we report dissect the molecular mechanism action three classes inhibitors differentiated binding...
Abstract Chronic cerebral hypoperfusion is a major cause of age-related vascular cognitive impairment. A well-characterised mouse model has shown that results in gliovascular and white matter damage impaired spatial working memory. In this study, we assessed whether cilostazol, phosphodiesterase III inhibitor, could protect against these changes. Adult, male C57Bl/6J mice were subjected to bilateral common carotid artery stenosis or sham operation fed normal cilostazol diet for three months....
11Beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) locally amplifies active glucocorticoids within specific tissues including in brain. In the hippocampus, 11β-HSD1 messenger RNA increases with aging. Here, we report significantly greater intrahippocampal corticosterone (CORT) levels aged wild-type (WT) mice during acquisition and retrieval trials a Y-maze than age-matched 11β-HSD1−/− mice, corresponding to impaired intact spatial memory, respectively. Acute stress applied young WT led...
Kynurenine 3-monooxygenase (KMO) is a therapeutically important target on the eukaryotic tryptophan catabolic pathway, where it converts L-kynurenine (Kyn) to 3-hydroxykynurenine (3-HK). We have cloned and expressed human form of this membrane protein as full-length GST-fusion in recombinant baculovirus expression system. An enriched preparation was used for directed screen approximately 78,000 compounds using RapidFire mass spectrometry (RF-MS) assay. The platform provides an automated...
Cyclophilins have been implicated in the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH). Pharmacological inhibition cyclophilin B isoform has potential to attenuate liver fibrosis MASH, but current inhibitors clinical trials lack selectivity. We previously reported novel tri-vector small-molecule inhibitor 1 that exhibited improved subtype selectivity by simultaneously engaging three pockets on surface cyclophilins. Here, we present structure–activity...