ORCID Profile
0000-0001-5241-3163
Current Organisations
The University of Auckland
,
The University of Hong Kong
,
University of Manchester
,
University of Oxford
,
The Academy of Medical Sciences
,
Guangzhou Institutes of Biomedicine and Health
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Publications
Synthesis of glycosylated 5-hydroxylysine, an important amino acid present in collagen-like proteins such as adiponectin
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C1OB06394D
Abstract: The synthesis of naturally occurring glycosylated (2S,5R)-hydroxylysine still remains a challenge. This perspective highlights the importance of this post-translationally modified amino acid residue in the observed bioactivity of collagen and related collagen-like proteins such as adiponectin, an important target for the treatment of type II diabetes. Strategies employed to date for the syntheses of (2S,5R)-hydroxylysine and the methods to effect glycosylation of this modified amino acid are also summarized herein.
Replacement of the CysA7–CysB7 disulfide bond with a 1,2,3-triazole linker causes unfolding in insulin glargine
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5OB00160A
Abstract: Two analogues of insulin glargine containing a 1,4-disubstituted 1,2,3-triazole group in place of the CysA7–CysB7 disulfide bond were prepared using CuAAC click chemistry to efficiently join the peptide chains.
Synthesis of stable isotope-labelled monolysyl advanced glycation endproducts
Publisher: Springer Science and Business Media LLC
Date: 16-04-2013
DOI: 10.1007/S00726-013-1498-9
Abstract: Advanced Glycation Endproducts (AGEs) are modified amino acids that form on proteins and are known to be implicated in the pathogenesis of diabetes and related diseases. Ready access to synthetic stable isotope-labelled AGEs allows for quantitative mass spectrometry studies to be undertaken, providing key insights into the roles AGEs play in the progression of such diseases. However, the majority of current syntheses of these compounds suffer from poor yields and lengthy procedures and are not suitable for the purposes required here. Here, we report robust syntheses of stable isotope-labelled monolysyl AGEs, N(ε)-(carboxymethyl)lysine, N(ε)-(carboxyethyl)lysine and pyrraline, that provide straightforward access to these compounds for quantitative amino acid analysis. This work will facilitate future investigations with these compounds and lead to a better understanding of the roles they play in diabetes and related diseases.
Robust Early Pregnancy Prediction of Later Preeclampsia Using Metabolomic Biomarkers
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
DOI: 10.1161/HYPERTENSIONAHA.110.157297
Abstract: Preecl sia is a pregnancy-specific syndrome that causes substantial maternal and fetal morbidity and mortality. The etiology is incompletely understood, and there is no clinically useful screening test. Current metabolomic technologies have allowed the establishment of metabolic signatures of preecl sia in early pregnancy. Here, a 2-phase discovery/validation metabolic profiling study was performed. In the discovery phase, a nested case-control study was designed, using s les obtained at 15±1 weeks’ gestation from 60 women who subsequently developed preecl sia and 60 controls taking part in the prospective Screening for Pregnancy Endpoints cohort study. Controls were proportionally population matched for age, ethnicity, and body mass index at booking. Plasma s les were analyzed using ultra performance liquid chromatography-mass spectrometry. A multivariate predictive model combining 14 metabolites gave an odds ratio for developing preecl sia of 36 (95% CI: 12 to 108), with an area under the receiver operator characteristic curve of 0.94. These findings were then validated using an independent case-control study on plasma obtained at 15±1 weeks from 39 women who subsequently developed preecl sia and 40 similarly matched controls from a participating center in a different country. The same 14 metabolites produced an odds ratio of 23 (95% CI: 7 to 73) with an area under receiver operator characteristic curve of 0.92. The finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of preecl sia offers insight into disease pathogenesis and offers the tantalizing promise of a robust presymptomatic screening test.
Regeneration of the Heart in Diabetes by Selective Copper Chelation
Publisher: American Diabetes Association
Date: 09-2004
DOI: 10.2337/DIABETES.53.9.2501
Abstract: Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A CuII-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and β1 integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.
Integrity of the Human Faecal Microbiota following Long-Term Sample Storage
Publisher: Public Library of Science (PLoS)
Date: 04-10-2016
Adiponectin Induces A20 Expression in Adipose Tissue to Confer Metabolic Benefit
Publisher: American Diabetes Association
Date: 04-09-2014
DOI: 10.2337/DB13-1835
Abstract: Obesity is a major risk factor for metabolic disease, with white adipose tissue (WAT) inflammation emerging as a key underlying pathology. We detail that mice lacking Reverbα exhibit enhanced fat storage without the predicted increased WAT inflammation or loss of insulin sensitivity. In contrast to most animal models of obesity and obese human patients, Reverbα−/− mice exhibit elevated serum adiponectin levels and increased adiponectin secretion from WAT explants in vitro, highlighting a potential anti-inflammatory role of this adipokine in hypertrophic WAT. Indeed, adiponectin was found to suppress primary macrophage responses to lipopolysaccharide and proinflammatory fatty acids, and this suppression depended on glycogen synthase kinase 3β activation and induction of A20. Attenuated inflammatory responses in Reverbα−/− WAT depots were associated with tonic elevation of A20 protein and ex vivo shown to depend on A20. We also demonstrate that adipose A20 expression in obese human subjects exhibits a negative correlation with measures of insulin sensitivity. Furthermore, bariatric surgery–induced weight loss was accompanied by enhanced WAT A20 expression, which is positively correlated with increased serum adiponectin and improved metabolic and inflammatory markers, including C-reactive protein. The findings identify A20 as a mediator of adiponectin anti-inflammatory action in WAT and a potential target for mitigating obesity-related pathology.
Expedient Synthesis of Peptides Containing N ε-Carboxymethyllysine
Publisher: Georg Thieme Verlag KG
Date: 06-06-2014
Postprandial response of adiponectin, interleukin-6, tumor necrosis factor-α, and C-reactive protein to a high-fat dietary load
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.NUT.2007.12.012
Abstract: Circulating levels of adiponectin are low in obesity and metabolic disorders associated with increasing fat mass including insulin resistance and dyslipidemia. Body fat stores may be positively related to intake of dietary fat, but little is known of mechanisms by which serum adiponectin may be regulated through diet. We investigated acute effects of a high-fat load and changes in fatty acid saturation on circulating adiponectin and associated mediators of inflammation including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP). A high-fat test meal (59 +/- 4 g fat 71% of energy as fat) containing a high ( approximately 71:29) or low ( approximately 55:45) ratio of saturated:unsaturated fatty acids was given at breakfast on two occasions. Blood s les were collected at 0 (baseline), 1, 3, and 6 h for measurement of adiponectin, IL-6, TNF-alpha, and high-sensitivity CRP. A fat-exclusion lunch, snack, and dinner were also given and blood s les collected at 10 and 24 h. Eighteen healthy, lean men completed the trial. There was no evidence of acute change in circulating adiponectin in response to the lipid bolus or a differential effect of fatty acid saturation on adiponectin, high-sensitivity CRP, or IL-6 (P > 0.05). IL-6 increased over 6 h on both treatments (time, P < 0.05). TNF-alpha decreased on the high saturated:unsaturated fatty acid treatment (treatment by time, P < 0.05). There were no significant correlations between circulating adiponectin and insulin on either dietary treatment in these normoglycemic subjects. Acute changes in the content of saturated and unsaturated fatty acids had no adverse effect on postprandial circulation of the adipose-related factors adiponectin, IL-6, TNF-alpha, or high-sensitivity CRP.
CHANGES IN THE MESENTERIC LYMPH PROTEOME INDUCED BY HEMORRHAGIC SHOCK
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2010
THE REDOX STATUS OF EXPERIMENTAL HEMORRHAGIC SHOCK AS MEASURED BY CYCLIC VOLTAMMETRY
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2010
Preptin, another peptide product of the pancreatic β-cell, is osteogenic in vitro and in vivo
Publisher: American Physiological Society
Date: 2007
DOI: 10.1152/AJPENDO.00642.2005
Abstract: Several hormones that regulate nutritional status also impact on bone metabolism. Preptin is a recently isolated 34-amino acid peptide hormone that is cosecreted with insulin and amylin from the pancreatic β-cells. Preptin corresponds to Asp 69 -Leu 102 of pro-IGF-II. Increased circulating levels of a pro-IGF-II peptide complexed with IGF-binding protein-2 have been implicated in the high bone mass phenotype observed in patients with chronic hepatitis C infection. We have assessed preptin's activities on bone. Preptin dose-dependently stimulated the proliferation (cell number and DNA synthesis) of primary fetal rat osteoblasts and osteoblast-like cell lines at periphysiological concentrations ( −11 M). In addition, thymidine incorporation was stimulated in murine neonatal calvarial organ culture, likely reflecting the proliferation of cells from the osteoblast lineage. Preptin did not affect bone resorption in this model. Preptin induced phosphorylation of p42 44 MAP kinases in osteoblastic cells in a dose-dependent manner (10 −8 -10 −10 M), and its proliferative effects on primary osteoblasts were blocked by MAP kinase kinase inhibitors. Preptin also reduced osteoblast apoptosis induced by serum deprivation, reducing the number of apoptotic cells by %. In vivo administration of preptin increased bone area and mineralizing surface in adult mice. These data demonstrate that preptin, which is cosecreted from the pancreatic β-cell with amylin and insulin, is anabolic to bone and may contribute to the preservation of bone mass observed in hyperinsulinemic states such as obesity.
Synthesis of Monolysyl Advanced Glycation Endproducts and Their Incorporation into Collagen Model Peptides
Publisher: American Chemical Society (ACS)
Date: 11-2012
DOI: 10.1021/OL302745F
Abstract: The synthesis of advanced glycation endproducts (AGEs), CML, CEL, and pyrraline and their incorporation into collagen model peptides is reported. AGEs are modified amino acids that form on proteins such as collagen and are thought to play a significant role in the pathogenesis of many diseases, particularly diabetes. The synthesis and incorporation of these compounds into synthetic peptides is a key step in developing model systems with which to investigate AGE-modified proteins.
Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis
Publisher: Elsevier BV
Date: 05-2011
No Evidence of an Effect of Alterations in Dietary Fatty Acids on Fasting Adiponectin Over 3 Weeks
Publisher: Wiley
Date: 03-2008
DOI: 10.1038/OBY.2007.97
Abstract: Little is known about the effects of alterations in fatty acid classes on adiponectin, a hormone secreted by the adipocyte known to be important in the development of diabetes and cardiovascular disease (CVD). Any factor, including diet, that may positively influence adiponectin gene expression or increase circulating levels might be useful for improving such metabolic abnormalities. We investigated the effects of alterations in dietary fatty acid saturation on fasting serum adiponectin and associated peptides. Double-blind, randomized, crossover, 2 x 3-week residential intervention trial where 18 mildly hyperlipidemic adult men were provided with a high saturated:unsaturated fat (SFA:USFA) and lower SFA:USFA treatment separated by an uncontrolled 4-week washout. Only fatty acid profile was altered between treatments. Fasting blood s les were collected on days 0, 1, 7, 14, 21, 22 of each intervention period for the measurement of adiponectin, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsC-RP), leptin, and ghrelin. Body weight was kept constant (+/-1 kg) throughout each treatment. There was no detectable difference in fasting adiponectin at baseline (mean day 0 + day 1) between the treatment groups (mean +/- s.d. high(SFA:USFA) = 7.0 +/- 1.7 vs. low(SFA:USFA) = 6.7 +/- 1.4 microg/ml, P > 0.05). There were neither significant between-treatment effects of fatty acid saturation (diet x time, P > 0.05) on serum adiponectin nor any significant between-treatment effects on serum TNF-alpha, IL-6, hsC-RP, leptin, or ghrelin (P > 0.05). Fasting serum adiponectin was not detectably affected by alterations in dietary fatty acid profile in mildly hyperlipidemic men. There was no evidence that an increase in SFA content of the diet significantly worsened fasting serum adiponectin over a 3-week intervention period.
A Label-free Selected Reaction Monitoring Workflow Identifies a Subset of Pregnancy Specific Glycoproteins as Potential Predictive Markers of Early-onset Pre-eclampsia
Publisher: Elsevier BV
Date: 11-2013
Site-specific cross-linking of collagen peptides by lysyl advanced glycation endproducts
Publisher: Royal Society of Chemistry (RSC)
Date: 2200
DOI: 10.1039/C4CC02003K
Abstract: Cross-linking lysyl AGEs were synthesised and incorporated into two types of collagen peptides and now enable detailed analysis of the effects these cross-links have on biological systems.
Physicochemical studies on the copper(ii ) binding by glycated collagen telopeptides
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4OB02536A
Abstract: The strong interaction between advanced glycation end-products and Cu( ii ) ions has been revealed using site-specifically glycated collagenous peptides.
Determination of triethylenetetramine (TETA) and its metabolites in human plasma and urine by liquid chromatography–mass spectrometry (LC–MS)
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.JCHROMB.2007.09.001
Abstract: A liquid chromatography-mass spectrometry (LC-MS) method has been developed to measure triethylenetetramine (TETA) and its metabolites in human s les. We identified two metabolites of TETA, N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine (DAT), the latter being novel. We further developed this LC-MS method for the measurement of TETA and these metabolites in human plasma and urine in a single injection. Separation of analytes was achieved on a cyano column using 15% acetonitrile, 85% water (18 M Omega), and 0.1% heptafluorobutyric acid as the mobile phase. Simultaneous MS detection was performed at [M+H]+ values of 147, 189, 231 and 245, corresponding to TETA, MAT, DAT, and N1-acetylspermine as the internal standard, respectively. This method was successfully applied to measure TETA, MAT and DAT in plasma and urine of humans receiving oral drug treatment.
Synthesis of the IGF-II-like hormone vesiculin using regioselective formation of disulfide bonds
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3OB40322J
Abstract: Diabetes mellitus, characterised by hyperglycemia and altered β-cell function, is an increasingly common disorder affecting millions of in iduals world-wide. While therapeutic regimens exist to manage the condition, diabetic in iduals remain prone to complications that are detrimental to both their length and quality of life. An improved understanding of the disease which may then enable development of new treatments is therefore a desirable goal. Vesiculin, a novel IGF-II-like protein was recently isolated from the secretory granules of murine β-cells, and preliminary studies indicate it is capable of signalling via the insulin receptor (IR)/insulin-like growth factor receptor 1(IGF1R) family giving it the potential to elicit both metabolic and mitogenic responses in the beta-cell. In order to facilitate further studies on this new member of the insulin-family of hormones, we undertook a chemical synthesis of the protein using regioselective disulfide bond formation.
Demonstration of a Hyperglycemia-Driven Pathogenic Abnormality of Copper Homeostasis in Diabetes and Its Reversibility by Selective Chelation
Publisher: American Diabetes Association
Date: 05-2005
DOI: 10.2337/DIABETES.54.5.1468
Abstract: We recently showed that treatment with the CuII-selective chelator, trientine, alleviates heart failure in diabetic rats, improves left ventricular hypertrophy in humans with type 2 diabetes, and increases urinary Cu excretion in both diabetic rats and humans compared with nondiabetic control subjects. In this study, we characterized the homeostasis of Cu and eight other nutritionally essential elements in diabetes under fully residential conditions in male subjects with type 2 diabetes and age-matched control subjects. We then probed elemental balance with oral trientine in a parallel-group, placebo-controlled study in these subjects. Before treatment, there were no detectable between-group differences in the balance of any element, although urinary output of several elements was greater in diabetic subjects. Mean extracellular superoxide dismutase (EC-SOD) activity was elevated in diabetic subjects, and its activity correlated strongly with the interaction between [Cu]serum and HbA1c. Trientine caused the Cu balance to become negative in diabetic subjects through elevated urinary Cu losses and suppressed elevated EC-SOD. Basal urinary Cu predicted urinary Cu losses during treatment, which caused extraction of systemic CuII. We suggest that cardiovascular complications in diabetes might be better controlled by therapeutic strategies that focus on lowering plasma glucose and loosely bound systemic CuII.
Incorporation of ‘click’ chemistry glycomimetics dramatically alters triple-helix stability in an adiponectin model peptide
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB01388D
Abstract: A striking decrease in thermal stability was observed upon incorporation of triazole-linked galactosylated-lysine into an adiponectin model peptide, suggesting possible applications of ‘click’ glycomimetics in bioengineering.
Using Mass Spectrometry to Detect, Differentiate, and Semiquantitate Closely Related Peptide Hormones in Complex Milieu: Measurement of IGF-II and Vesiculin
Publisher: The Endocrine Society
Date: 03-2015
DOI: 10.1210/EN.2014-1593
Abstract: The search for an islet β-cell growth factor has been a key objective in recent diabetes research, because the ability to regenerate and/or protect the functioning β-cell population in patients could result in a great advancement for diabetes treatment. IGF-I and IGF-II are known to play crucial roles in fetal growth and prenatal development, and there is growing evidence that IGF-II increases β-cell proliferation and survival in vitro and in vivo. A search for the source of IGF-II–like immunoreactivity in isolated β-cell secretory granules from the murine cell line βTC6-F7 revealed a novel 2-chain IGF-II–derived peptide, which we named vesiculin and which has been shown to be a full insulin agonist. Here, we present a liquid chromatography–tandem mass spectrometry method that enables selective detection and semiquantitation of the highly related IGF-II and vesiculin molecules. We have used this method to measure these 2 peptides in conditioned media from 2 β-cell lines, produced under increasing glucose concentrations. This technique detected both IGF-II and vesiculin in media conditioned by MIN6 and βTC6-F7 cells at levels in the range of 0 to 6 μM (total insulin, 80–450 μM) and revealed a glucose-stimulated increase in insulin, IGF-II, and vesiculin. IGF-II was detected in adult human and neonatal mouse serum in high levels, but vesiculin was not present. The methodology we present herein has utility for detecting and differentiating active peptides that are highly related and of low abundance.
Effect of high-fat meals and fatty acid saturation on postprandial levels of the hormones ghrelin and leptin in healthy men
Publisher: Springer Science and Business Media LLC
Date: 24-08-2005
Abstract: Ghrelin and leptin play a role in control of food intake and adiposity but mechanisms regulating these hormones in man are poorly defined and evidence that dietary fats may have adverse effects is inconclusive. We investigated whether high-fat meals, which differed in saturated fatty acid (SFA) content acutely modified these hormones. Randomised, double-blind, crossover trial. A high-fat (HF) test meal (59 +/- 4 g fat 71% of energy as fat) was given for breakfast on two occasions. Meals comprised either high (approximately 70:30) or low (approximately 55:45) saturated:unsaturated fatty acid (SFA:USFA) ratio. Fasting and postprandial measurements of serum total ghrelin (RIA), leptin (enzyme-linked immunosorbent assay (ELISA)) and insulin (RIA) were made over 6 h. Postprandial measurements were also made at 10 and 24 h following a fat-exclusion lunch, snack and dinner. A total of 18 lean, healthy men. There was no significant effect of the fatty meal (time, P > 0.05), nor a differential effect of SFA:USFA ratio (treatment*time, P > 0.05) on ghrelin over 6h. Leptin decreased in response to both HF treatments (time, P 0.05). There was no significant correlation between ghrelin or leptin and circulating insulin (P>0.05). We conclude that HF diets may adversely effect serum leptin, although the circadian decrease may account in part for this response. Increasing dietary SFAs had no deleterious effects on leptin or total ghrelin.
Evidence That Multiple Defects in Lipid Regulation Occur before Hyperglycemia during the Prodrome of Type-2 Diabetes
Publisher: Public Library of Science (PLoS)
Date: 03-09-2014
The proteome of rodent mesenteric lymph
Publisher: American Physiological Society
Date: 11-2008
Abstract: Mesenteric lymph contributes to normal homeostasis and has an emerging role in the pathogenesis of multiple organ dysfunction syndrome. The aim of this study was to define the proteome of normal rodent mesenteric lymph in the fasted and fed states. Eight male Wistar rats fed a standard rodent diet were randomized to two groups. Group 1 (fasted, n = 4) were fasted for 24 h before anesthetized collection of mesenteric lymph. Group 2 (fed, n = 4) were allowed ad libitum access to food before lymph collection. Mesenteric lymph was subjected to proteomic analysis using iTRAQ and liquid chromatography-tandem mass spectrometry (LC-MS/MS). One hundred fifty proteins, including 26 hypothetical proteins, were identified in this study. All proteins were identified in lymph from both the fasted and fed states. The relative distribution profiles of protein functional classes in the mesenteric lymph differed significantly from that reported for plasma. The most abundant classes identified in lymph were protease inhibitors (16%) and proteins related to innate immunity (12%). In conclusion, this study provides the first detailed description of the normal mesenteric lymph proteome in the fed and fasted states using iTRAQ and LC-MS/MS.
Characterization of proteomic changes in cardiac mitochondria in streptozotocin-diabetic rats using iTRAQ™ isobaric tags
Publisher: Wiley
Date: 06-2007
Abstract: Diabetes now affects more than 5% of the world's population and heart failure is the most common cause of death amongst diabetic patients. Accumulating evidence supports a view that myocardial mitochondrial structural and functional changes are central to the onset of diabetic heart failure, but the exact nature of these changes at the proteomic level remains unclear.Here we report on proteomic changes in diabetic rat heart mitochondria following 120 days of streptozotocin-diabetes using the recently developed iTRAQ™ labeling method, which permits quantification of proteins directly from complex mixtures, bypassing the limitations associated with gel-based methods such as 2-DE. Of 252 unique proteins identified, 144 were represented in at least three of six in idual paired experiments. Relative amounts of 65 proteins differed significantly between the groups, confirming that the cardiac mitochondrial proteome is indeed impacted by diabetes. The most significant changes were increased protein levels of enzymes involved in mitochondrial oxidation of long-chain fatty acids, which was also confirmed by enzyme assays, and decreased levels of multiple enzymes involved in oxidative phosphorylation and catabolism of short-chain fatty acids and branched-chain amino acids. We also found significant changes in levels of several enzymes linked to oxidative stress.
Related Organisations
University Of Manchester
Location: United Kingdom of Great Britain and Northern Ireland
University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
The Academy Of Medical Sciences
Location: United Kingdom of Great Britain and Northern Ireland
John Radcliffe Hospital
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Garth Cooper.