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1.
Mar Pollut Bull ; 142: 290-302, 2019 May.
Article in English | MEDLINE | ID: mdl-31232306

ABSTRACT

The potential risk to the marine environment of oil release from potentially polluting wrecks (PPW) is increasingly being acknowledged, and in some instances remediation actions have been required. However, where a PPW has been identified, there remains a great deal of uncertainty around the environmental risk it may pose. Estimating the likelihood of a wreck to release oil and the threat to marine receptors remains a challenge. In addition, removing oil from wrecks is not always cost effective, so a proactive approach is recommended to identify PPW that pose the greatest risk to sensitive marine ecosystems and local economies and communities. This paper presents a desk-based assessment approach which addresses PPW, and the risk they pose to environmental and socio-economic marine receptors, using modelled scenarios and a framework and scoring system. This approach can be used to inform proactive management options for PPW and can be applied worldwide.


Subject(s)
Petroleum Pollution , Risk Assessment/standards , Ships , Water Pollution, Chemical , Accidents , Ecosystem , Environmental Monitoring , Seawater , Uncertainty
2.
BMC Genomics ; 19(1): 188, 2018 03 09.
Article in English | MEDLINE | ID: mdl-29523084

ABSTRACT

BACKGROUND: Noninvasive biomarkers are urgently needed for patients with nonalcoholic steatohepatitis (NASH) to assist in diagnosis, monitoring disease progression and assessing treatment response. Recently several exploratory studies showed that circulating level of microRNA is associated with NASH and correlated with disease severity. Although these data were encouraging, the application of circulating microRNA as biomarkers for patient screening and stratification need to be further assessed under well-controlled conditions. RESULTS: The expression of circulating microRNAs were profiled in diet-induced NASH progression and regression models to assess the diagnostic and prognostic values and the translatability between preclinical mouse model and men. Since these mice had same genetic background and were housed in the same conditions, there were minimal confounding factors. Histopathological lesions were analyzed at distinct disease progression stages along with microRNA measurement which allows longitudinal assessment of microRNA as NASH biomarkers. Next, differentially expressed microRNAs were identified and validated in an independent cohorts of animals. Thirdly, these microRNAs were examined in a NASH regression model to assess whether they would respond to NASH treatment. MicroRNA profiling in two independent cohorts of animals validated the up-regulation of 6 microRNAs (miR-122, miR-192, miR-21, miR-29a, miR-34a and miR-505) in NASH mice, which was designated as the circulating microRNA signature for NASH. The microRNA signature could accurately distinguish NASH mice from lean mice, and it responded to chow diet treatment in a NASH regression model. To further improve the performance of microRNA-based biomarker, a new composite biomarker was proposed, which consists of miR-192, miR-21, miR-505 and ALT. The new composite biomarker outperformed the microRNA signature in predicting NASH mice which had NAS > 3, and deserves further validations in large scale studies. CONCLUSION: The present study supported the translation of circulating microRNAs between preclinical models and humans in NASH pathogenesis and progression. The microRNA-based composite biomarker may be used for non-invasive diagnosis, clinical monitoring and assessing treatment response for NASH.


Subject(s)
Biomarkers/blood , Circulating MicroRNA/genetics , Gene Expression Profiling , Liver/metabolism , Non-alcoholic Fatty Liver Disease/diagnosis , Animals , Circulating MicroRNA/blood , Disease Progression , Humans , Male , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/genetics , Prognosis
3.
Mar Pollut Bull ; 129(2): 609-614, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29102073

ABSTRACT

The UK Marine Management Organisation (MMO) tasked the Centre for Environment, Fisheries & Aquaculture Science (Cefas) with reviewing the current UK dispersant efficacy testing procedures. The aim was to identify possibilities to increase standardisation, improve health and safety performance and explore harmonisation possibilities with international dispersant efficacy testing procedures. The US EPA 'Baffled Flask Test' (BFT) was adopted, implemented and validated as a new standard method in the UK. The outputs from this study suggest that dispersant efficacy results from the adopted BFT test and the currently used protocol are in a similar range and results presented by the US EPA. As a result, the transition to the adopted BFT test will require minimal changes in the assessment of the results or reporting and increase harmonisation between tests used in the UK and North America.


Subject(s)
Environmental Restoration and Remediation/methods , Petroleum Pollution/analysis , Petroleum/analysis , Surface-Active Agents/chemistry , Water Pollutants, Chemical/analysis , Environmental Restoration and Remediation/standards , Models, Theoretical , Surface-Active Agents/standards , United Kingdom
4.
Mar Pollut Bull ; 120(1-2): 51-57, 2017 Jul 15.
Article in English | MEDLINE | ID: mdl-28477985

ABSTRACT

Small-scale pollution events involve the release of potentially harmful substances into the marine environment. These events can affect all levels of the ecosystem, with damage to both fauna and flora. Numerous reporting structures are currently available to document spills, however there is a lack of information on small-scale events due to their magnitude and patchy distribution. To this end, volunteers may provide a useful tool in filling this data gap, especially for coastal environments with a high usage by members of the public. The potential for citizen scientists to record small-scale pollution events is explored using the UK as an example, with a focus on highlighting methods and issues associated with using this data source. An integrated monitoring system is proposed which combines citizen science and traditional reporting approaches.


Subject(s)
Environmental Monitoring , Environmental Pollution , Volunteers , Ecosystem , Humans , United Kingdom
5.
J Med Chem ; 60(12): 4932-4948, 2017 06 22.
Article in English | MEDLINE | ID: mdl-28537398

ABSTRACT

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Azetidines/pharmacology , Enzyme Inhibitors/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Actins/antagonists & inhibitors , Adamantane/administration & dosage , Adamantane/chemistry , Adamantane/pharmacology , Administration, Oral , Animals , Azetidines/administration & dosage , Azetidines/chemistry , Biological Availability , Crystallography, X-Ray , Dogs , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Female , Half-Life , Humans , Hypothalamo-Hypophyseal System/drug effects , Inhibitory Concentration 50 , Macaca fascicularis , Male , Mice, Obese , Rats , Structure-Activity Relationship
6.
Toxicol Pathol ; 43(6): 825-37, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26085543

ABSTRACT

Glucokinase (GK) catalyzes the initial step in glycolysis and is a key regulator of glucose homeostasis. Therefore, glucokinase activators (GKa) have potential benefit in treating type 2 diabetes. Administration of a Bristol-Myers Squibb GKa (BMS-820132) to healthy euglycemic Sprague-Dawley (SD) rats and beagle dogs in 1 mo toxicology studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures comparable to those expected at therapeutic clinical exposures. To investigate whether these adverse effects were secondary to exaggerated pharmacology (prolonged hypoglycemia), BMS-820132 was administered daily to male Zucker diabetic fatty (ZDF) rats for 1 mo. ZDF rats are markedly hyperglycemic and insulin resistant. BMS-820132 did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1 mo toxicology studies at exposures that exceeded those observed in SD rats and dogs. This indicates that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GK activation. This study indicates that ZDF rats, with conventional toxicity studies, are a useful disease model for testing antidiabetic agents and determining toxicities that are independent of prolonged hypoglycemia.


Subject(s)
Diabetes Mellitus/genetics , Enzyme Activators/toxicity , Hypoglycemia/chemically induced , Hypoglycemic Agents/toxicity , Rats, Zucker/metabolism , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Diabetes Mellitus/pathology , Dogs , Eating/drug effects , Enzyme Activators/pharmacokinetics , Glucokinase/genetics , Hypoglycemia/pathology , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Insulin/blood , Insulin Resistance/genetics , Male , Rats , Species Specificity , Toxicokinetics
7.
Mar Pollut Bull ; 89(1-2): 451-454, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25444627

ABSTRACT

Concentrations of polycyclic aromatic hydrocarbons were determined in edible tissues of fish species consumed by the islanders of St Helena to assess any risk to human health posed by oil leaking from an historic wreck. Samples were collected from the vicinity of the wreck site and at two reference locations at which fishing activity occurs. Summed PAH concentrations ranged from 2.2 to 20 µg kg(-1) wet weight, and no PAHs with more than 4 fused rings were detected. All concentrations of the four PAH used as a basis for assessment in relation to health risks to human consumers of foods within the EU (benz[a]anthracene, benzo[a]pyrene, benzo[b]fluoranthene and chrysene) were<0.1 µg kg(-1) wet weight and raised no concerns. Additionally, concentrations were calculated as the benzo[a]pyrene toxic equivalency quotient and found to be well below the level of concern (0 to 0.05 µg kg(-1) wet weight benzo[a]pyrene equivalents).


Subject(s)
Environmental Exposure , Food Contamination/analysis , Petroleum Pollution , Polycyclic Aromatic Hydrocarbons/analysis , Seafood/analysis , Water Pollutants, Chemical/analysis , Animals , Atlantic Islands , Environmental Monitoring , Fishes , Humans , Polycyclic Aromatic Hydrocarbons/metabolism , Water Pollutants, Chemical/metabolism
8.
Mar Pollut Bull ; 82(1-2): 11-8, 2014 May 15.
Article in English | MEDLINE | ID: mdl-24576390

ABSTRACT

Understanding the fate and effects of marine spills is essential if the scientific and response communities are to develop best practices. The effective deployment of environmental monitoring activity can be complex and requires planning and coordination but the levels of preparedness to deliver the necessary expertise, coordination and funding are often low. This paper identifies and describes the importance of 8 principles of effective post-spill monitoring programmes. These principles are then used in the assessment of monitoring preparedness through the generation of a monitoring preparedness assessment score (MPAS). This approach can be used by local, regional or national authorities to establish the level of preparedness for environmental monitoring and prioritise areas for improvement. It also has value to responders, policy makers, environmental scientists and planners as a tool to assess preparedness and capability for specific scenarios. The approach is demonstrated through the assessment of previous incidents and potential future scenarios.


Subject(s)
Environmental Monitoring/methods , Petroleum Pollution/analysis , Water Pollutants, Chemical/analysis , Water Pollution, Chemical/analysis , Environmental Exposure , Oceans and Seas , Risk Assessment , United Kingdom
9.
Bioorg Med Chem Lett ; 24(2): 654-60, 2014 Jan 15.
Article in English | MEDLINE | ID: mdl-24360604

ABSTRACT

A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11ß-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11ß-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11ß-HSD1 with a favorable development profile.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/chemical synthesis , Tetrazoles/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adamantane/pharmacology , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Mice , Mice, Transgenic , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Protein Structure, Secondary , Structure-Activity Relationship , Tetrazoles/pharmacology
10.
J Med Chem ; 56(18): 7343-57, 2013 Sep 26.
Article in English | MEDLINE | ID: mdl-23964740

ABSTRACT

Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.


Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Design , Pyrroles/chemistry , Pyrroles/pharmacology , Acetamides/chemical synthesis , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Catalytic Domain , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Glucose Tolerance Test , Humans , Male , Mice , Models, Molecular , Pyrroles/chemical synthesis , Substrate Specificity
11.
Regul Pept ; 186: 26-35, 2013 Sep 10.
Article in English | MEDLINE | ID: mdl-23850796

ABSTRACT

Dipeptidyl peptidases (DPPs) are proteolytic enzymes that regulate many physiological systems by degrading signaling peptides. DPP8 and DPP9 are distinct from DPP4 in sequence, cellular localization and expression levels, thus implying distinct functions. However, DPP8 and DPP9 expression needs further delineation. We evaluated DPP4, DPP8 and DPP9 expression using three independent methods at the mRNA, protein, and functional levels to better understand the local physiological contribution of each enzyme. Sprague Dawley rats and cynomolgus monkeys were selected for DPP4, DPP8 and DPP9 expression profiling to represent animal species commonly utilized for drug preclinical safety evaluation. A novel Xhibit assay of DPP protease activity was applied in addition to newly available antibodies for immunohistochemical localization. This combined approach can facilitate a functional evaluation of protease expression, which is important for understanding physiological relevance. Few inter-species differences were observed. Tissue mRNA and protein levels generally correlated to functional DPP4 and DPP8/9 enzymatic activity. All three proteins were seen in epithelial cells, lymphoid cells and some endothelial and vascular smooth muscle cells. Combined DPP8/DPP9 enzymatic activity was uniformly intracellular across tissues at approximately 10-fold lower levels than non-renal DPP4. Consistent levels of each DPP were detected among most non-renal tissues in rats and monkeys. DPP4 was ubiquitous, principally detected on cell membranes of epithelial and endothelial cells and was greatest in the kidney. The expression patterns suggest that DPP8 and DPP9 may act similarly across tissues, and that their actions might in part overlap with DPP4.


Subject(s)
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism , Kidney/enzymology , Amino Acid Sequence , Animals , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Female , Gene Expression , Macaca fascicularis , Male , Molecular Sequence Data , Organ Specificity , Pancreas/enzymology , Rats , Rats, Sprague-Dawley , Species Specificity
12.
Bioorg Med Chem Lett ; 23(6): 1622-5, 2013 Mar 15.
Article in English | MEDLINE | ID: mdl-23416006

ABSTRACT

Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors.


Subject(s)
Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Piperidines/chemistry , Pyrrolidines/chemistry , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/metabolism , Humans , Hydrogen-Ion Concentration , Protein Binding , Pyrrolidines/chemical synthesis , Pyrrolidines/metabolism , Structure-Activity Relationship , Temperature
13.
Cell Metab ; 17(1): 141-52, 2013 Jan 08.
Article in English | MEDLINE | ID: mdl-23312289

ABSTRACT

Obesity is a highly heritable disease driven by complex interactions between genetic and environmental factors. Human genome-wide association studies (GWAS) have identified a number of loci contributing to obesity; however, a major limitation of these studies is the inability to assess environmental interactions common to obesity. Using a systems genetics approach, we measured obesity traits, global gene expression, and gut microbiota composition in response to a high-fat/high-sucrose (HF/HS) diet of more than 100 inbred strains of mice. Here we show that HF/HS feeding promotes robust, strain-specific changes in obesity that are not accounted for by food intake and provide evidence for a genetically determined set point for obesity. GWAS analysis identified 11 genome-wide significant loci associated with obesity traits, several of which overlap with loci identified in human studies. We also show strong relationships between genotype and gut microbiota plasticity during HF/HS feeding and identify gut microbial phylotypes associated with obesity.


Subject(s)
Diet, High-Fat , Intestinal Mucosa/microbiology , Metagenome , Obesity/genetics , Animals , Body Composition , Dietary Carbohydrates , Genome , Genome-Wide Association Study , Humans , Mice , Obesity/pathology , Quantitative Trait Loci
14.
BMC Pharmacol ; 12: 2, 2012 Apr 04.
Article in English | MEDLINE | ID: mdl-22475049

ABSTRACT

BACKGROUND: Dipeptidylpeptidase 4 (DPP4) inhibitors have clinical benefit in patients with type 2 diabetes mellitus by increasing levels of glucose-lowering incretin hormones, such as glucagon-like peptide -1 (GLP-1), a peptide with a short half life that is secreted for approximately 1 hour following a meal. Since drugs with prolonged binding to their target have been shown to maximize pharmacodynamic effects while minimizing drug levels, we developed a time-dependent inhibitor that has a half-life for dissociation from DPP4 close to the duration of the first phase of GLP-1 release. RESULTS: Saxagliptin and its active metabolite (5-hydroxysaxagliptin) are potent inhibitors of human DPP4 with prolonged dissociation from its active site (Ki = 1.3 nM and 2.6 nM, t1/2 = 50 and 23 minutes respectively at 37°C). In comparison, both vildagliptin (3.5 minutes) and sitagliptin ( < 2 minutes) rapidly dissociated from DPP4 at 37°C. Saxagliptin and 5-hydroxysaxagliptin are selective for inhibition of DPP4 versus other DPP family members and a large panel of other proteases, and have similar potency and efficacy across multiple species.Inhibition of plasma DPP activity is used as a biomarker in animal models and clinical trials. However, most DPP4 inhibitors are competitive with substrate and rapidly dissociate from DPP4; therefore, the type of substrate, volume of addition and final concentration of substrate in these assays can change measured inhibition. We show that unlike a rapidly dissociating DPP4 inhibitor, inhibition of plasma DPP activity by saxagliptin and 5-hydroxysaxagliptin in an ex vivo assay was not dependent on substrate concentration when substrate was added rapidly because saxagliptin and 5-hydroxysaxagliptin dissociate slowly from DPP4, once bound. We also show that substrate concentration was important for rapidly dissociating DPP4 inhibitors. CONCLUSIONS: Saxagliptin and its active metabolite are potent, selective inhibitors of DPP4, with prolonged dissociation from its active site. They also demonstrate prolonged inhibition of plasma DPP4 ex vivo in animal models, which implies that saxagliptin and 5-hydroxysaxagliptin would continue to inhibit DPP4 during rapid increases in substrates in vivo.


Subject(s)
Adamantane/analogs & derivatives , Dipeptides/metabolism , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/metabolism , Hypoglycemic Agents/metabolism , Adamantane/metabolism , Algorithms , Animals , Artifacts , Cloning, Molecular , Dipeptidases/metabolism , Dipeptidyl Peptidase 4/blood , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism , Glucagon-Like Peptide 1/metabolism , Humans , Indicators and Reagents , Kinetics , Macaca fascicularis , Nitriles/metabolism , Protein Binding , Pyrazines/metabolism , Pyrrolidines/metabolism , Sitagliptin Phosphate , Species Specificity , Triazoles/metabolism , Vildagliptin
15.
Article in English | MEDLINE | ID: mdl-22349123

ABSTRACT

A liquid chromatography and tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine the concentrations of saxagliptin (Onglyza™, BMS-477118) and its major active metabolite, 5-hydroxy saxagliptin to support pharmacokinetic analyses in clinical studies. The dynamic range of the assay was 0.1-50 ng/mL for saxagliptin and 0.2-100 ng/mL for 5-hydroxy saxagliptin. Protein precipitation (PPT) with acetonitrile was used to extract the analytes from plasma matrix before injecting on an Atlantis(®) dC18 column (50 mm × 2.1 mm, 5 µm) for LC-MS/MS analysis. The sample pre-treatment process was carefully controlled to disrupt DPP4-specific binding and non-specific binding observed at lower concentrations. The recoveries for both analytes were >90%. The assay was selective, rugged and reproducible; storage stability of at least 401 days at -20°C was demonstrated. Under these chromatographic conditions, the isomers of saxagliptin and 5-hydroxy saxagliptin were chromatographically separated from saxagliptin and 5-hydroxy saxagliptin. The assay has been used to support multiple clinical studies and regulatory approvals.


Subject(s)
Adamantane/analogs & derivatives , Chromatography, Liquid/methods , Dipeptides/blood , Tandem Mass Spectrometry/methods , Adamantane/blood , Adamantane/chemistry , Adamantane/pharmacokinetics , Dipeptides/chemistry , Dipeptides/pharmacokinetics , Drug Stability , Humans , Reproducibility of Results , Sensitivity and Specificity , Stereoisomerism
17.
Bioorg Med Chem Lett ; 21(22): 6646-51, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-21996520

ABSTRACT

Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 µM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 µmol/kg in ob/ob mice.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Animals , Catalytic Domain , Diabetes Mellitus/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Humans , Insulin/blood , Insulin/metabolism , Mice , Mice, Inbred C57BL , Models, Molecular , Pyridines/pharmacokinetics , Pyrroles/chemistry , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Stereoisomerism
18.
Ecotoxicol Environ Saf ; 74(8): 2245-51, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21885125

ABSTRACT

Toxic equivalency factors/quotients (TEF/TEQs) express the toxicity of complex mixtures. For PAHs, TEF values are available for assessing their carcinogenic potential and are expressed as benzo[a]pyrene equivalents. This study develops a similar approach for their acute toxicity in sediments. Acute toxicity (10 day EC50) values were generated using the marine amphipod Corophium volutator bioassay for twelve low molecular weight PAHs. The results ranged from 24 to > 1000 mg/Kg sediment dry weight for 4-methyldibenzothiophene and anthracene, respectively. Phenanthrene was used as the reference compound (TEF=1) and so the TEQ values derived are expressed as phenanthrene equivalents. In order to illustrate the applicability of this approach to the development of marine indicators we plotted TEQ values for acute toxicity to UK environmental monitoring data. Further work is required to validate the TEF values produced and to extend the TEQ approach to include a wider range of low molecular weight PAHs.


Subject(s)
Environmental Monitoring/methods , Geologic Sediments/chemistry , Polycyclic Aromatic Hydrocarbons/toxicity , Toxicity Tests/methods , Water Pollutants, Chemical/toxicity , Amphipoda/drug effects , Animals , Benzo(a)pyrene/toxicity , Biological Assay , Carcinogens/toxicity , Environmental Monitoring/standards , Phenanthrenes/toxicity , Polycyclic Aromatic Hydrocarbons/standards , Risk Assessment , Toxicity Tests/standards , Water Pollutants, Chemical/standards
20.
Br J Nutr ; 105(7): 1036-46, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21144093

ABSTRACT

The objective of the present study was to investigate whether weight loss is associated with changes in serum concentrations of lutein (L) and zeaxanthin (Z), and/or macular pigment optical density (MPOD). We recruited 104 overweight subjects into this randomised controlled weight loss study. For the intervention group (I group), weight was assessed weekly and body composition, including BMI (kg/m2) and body fat (kg and percentage), was assessed at baseline, 6 and 12 months. Weight loss was encouraged using dietary and exercise programmes. MPOD was measured by heterochromatic flicker photometry and serum concentrations of L and Z by HPLC (at baseline, 1, 3, 6 and 12 months). The control (C) group was assessed at baseline and 12 months. Repeated-measures ANOVA (RMA) demonstrated significant weight loss in the I group over the study period (P = 0·000). There was no significant weight change in the C group (P = 0·993). RMA of dietary L and Z, serum L and Z, and MPOD demonstrated no significant time or time × group interaction effect in any of these parameters (P>0·05 for all), with the exception of a significant decrease in the dietary intake of Z seen in both groups, over the study period (P < 0·05). There was a positive and significant relationship between body fat loss (kg) and increase in serum concentrations of L in the I group (r 0·521; P = 0·006). Our finding that a reduction in body composition (e.g. fat mass) is related to increases in serum concentrations of L is consistent with the hypothesis that body fat acts as a reservoir for this carotenoid, and that weight loss can positively influence circulating carotenoid levels.


Subject(s)
Adipose Tissue/metabolism , Lutein/blood , Overweight/blood , Retinal Pigments/physiology , Weight Loss/physiology , Xanthophylls/blood , Adult , Analysis of Variance , Body Composition , Diet, Reducing , Exercise , Female , Humans , Male , Middle Aged , Overweight/complications , Overweight/therapy , Photometry , Xanthophylls/administration & dosage , Zeaxanthins
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