| 1. |
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| 2. |
- Christopoulos, Arthur, et al.
(författare)
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THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.
- 2021
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Ingår i: British journal of pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 178 Suppl 1
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Forskningsöversikt (refereegranskat)abstract
- The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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| 3. |
- Alexander, Stephen P. H., et al.
(författare)
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The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
- 2023
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Ingår i: BRITISH JOURNAL OF PHARMACOLOGY. - : British pharmacological society. - 0007-1188 .- 1476-5381. ; 180
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Tidskriftsartikel (refereegranskat)abstract
- The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at . G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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| 4. |
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| 5. |
- Chapnick, J. V., et al.
(författare)
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Techniques for multimodality image registration
- 1993
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Ingår i: Bioengineering, Proceedings of the Northeast Conference. - 0780309251 ; , s. 221-222
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Konferensbidrag (refereegranskat)abstract
- The authors describe the development of techniques used for cross-modality correlation of medical images. To accomplish this goal, software routines were developed which automate and standardize the comparison of images within and between three-dimensional tomographic imaging modalities. Data from phantoms and clinical studies reflect the success of this technique.
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| 8. |
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| 9. |
- Falkén, Y., et al.
(författare)
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Actions of prolonged ghrelin infusion on gastrointestinal transit and glucose homeostasis in humans
- 2010
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 22:6, s. e192-e200
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Tidskriftsartikel (refereegranskat)abstract
- Background Ghrelin is produced by enteroendocrine cells in the gastric mucosa and stimulates gastric emptying in healthy volunteers and patients with gastroparesis in short-term studies. The aim of this study was to evaluate effects of intravenous ghrelin on gastrointestinal motility and glucose homeostasis during a 6-h infusion in humans. Methods Ghrelin (15 pmol kg−1 min−1) or saline was infused intravenously for 360 min after intake of radio-opaque markers, acetaminophen, and lactulose after a standardized breakfast in 12 male volunteers. Gastric emptying, orocecal transit, colonic transit, postprandial plasma concentrations of glucose, insulin, glucagon-like peptide-1 (GLP-1), and peptide YY were assessed. In vitro studies of gastrointestinal muscle contractility were performed. Key Results The gastric emptying rate was faster for ghrelin compared to saline (P = 0.002) with a shorter half-emptying time (50.3 ± 3.9 vs 59.9 ± 4.4 min, P = 0.004). There was no effect of ghrelin on orocecal or colonic transit. Postprandial elevations of plasma glucose, insulin, and GLP-1 occurred 15 min earlier and were higher with ghrelin. The insulinogenic index did not change during ghrelin infusion. Basal in vitro contractility was unaffected by ghrelin. Conclusions & Inferences The effect of a 6-h ghrelin infusion on gastrointestinal motility is limited to the stomach without affecting orocecal or colonic transit. Plasma glucose, insulin, and GLP-1 are elevated postprandially, probably as a result of the hastened gastric emptying. Changes in glucose homeostasis as a consequence of stimulated gastric emptying and hormone release, need to be taken into account in the use of pharmacological stimulants for the treatment of motility disorders.
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| 10. |
- Farmer, Adam D, et al.
(författare)
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Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans
- 2015
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Ingår i: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 593:5, s. 1183-1196
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: Nausea is a highly individual and variable experience. The reasons for this variability are incompletely understood although psychophysiological factors have been proposed. Herein we describe objective psychophysiological changes induced by the subjective sensation of motion sickness. In comparison to subjects who did not develop nausea, nausea-sensitive subjects demonstrated electrogastrographic and autonomic changes, which included an increase in sympathetic nervous system activity with a concomitant reduction in parasympathetic activity. Furthermore, differences were also evident in plasma ghrelin, and subcortical and cortical activity. These data have a number of important implications for future research examining the physiological mechanisms that underlie nausea: ○The physiological, hormonal and cortical patterns identified herein represent potential biomarkers of the physiological mechanisms of nausea. ○Reverse translation of the physiological factors identified may facilitate refinement of animal models used to investigate novel anti-emetic agents and emetic liability of candidate drugs, increasing their validity and translation of finding to humans.ABSTRACT: An integrated understanding of the physiological mechanisms involved in the genesis of nausea remains lacking. We aimed to describe the psychophysiological changes accompanying visually induced motion sickness, using a motion video, hypothesizing that differences would be evident between subjects who developed nausea in comparison to those who did not. A motion, or a control, stimulus was presented to 98 healthy subjects in a randomized crossover design. Validated questionnaires and a visual analogue scale (VAS) were used for the assessment of anxiety and nausea. Autonomic and electrogastrographic activity were measured at baseline and continuously thereafter. Plasma vasopressin and ghrelin were measured in response to the motion video. Subjects were stratified into quartiles based on VAS nausea scores, with the upper and lower quartiles considered to be nausea sensitive and resistant, respectively. Twenty-eight subjects were exposed to the motion video during functional neuroimaging. During the motion video, nausea-sensitive subjects had lower normogastria/tachygastria ratio and cardiac vagal tone but higher cardiac sympathetic index in comparison to the control video. Furthermore, nausea-sensitive subjects had decreased plasma ghrelin and demonstrated increased activity of the left anterior cingulate cortex. Nausea VAS scores correlated positively with plasma vasopressin and left inferior frontal and middle occipital gyri activity and correlated negatively with plasma ghrelin and brain activity in the right cerebellar tonsil, declive, culmen, lingual gyrus and cuneus. This study demonstrates that the subjective sensation of nausea is associated with objective changes in autonomic, endocrine and brain networks, and thus identifies potential objective biomarkers and targets for therapeutic interventions.
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| 11. |
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| 12. |
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| 13. |
- Noz, Marilyn E., et al.
(författare)
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Graphical interface for medical image processing
- 1993
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Ingår i: Journal of medical systems. - 0148-5598 .- 1573-689X. ; 17:1, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a graphical interface which allows users of varying levels of computer experience and proficiency to manipulate medical image-processing data with "point-and-click" ease. The power which had formerly been associated with protocols and shell scripts has been combined with the flexibility and "user-friendliness" of buttons and dialog boxes.
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| 14. |
- Raval, Aparna, et al.
(författare)
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Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia
- 2007
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 129:5, s. 879-890
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Tidskriftsartikel (refereegranskat)abstract
- The heritability of B cell chronic lymphocytic leukemia (CLL) is relatively high; however, no predisposing mutation has been convincingly identified. We show that loss or reduced expression of death-associated protein kinase 1 (DAPK1) underlies cases of heritable predisposition to CLL and the majority of sporadic CLL. Epigenetic silencing of DAPK1 by promoter methylation occurs in almost all sporadic CLL cases. Furthermore, we defined a disease haplotype, which segregates with the CLL phenotype in a large family. DAPK1 expression of the CLL allele is downregulated by 75% in germline cells due to increased HOXB7 binding. In the blood cells from affected family members, promoter methylation results in additional loss of DAPK1 expression. Thus, reduced expression of DAPK1 can result from germline predisposition, as well as epigenetic or somatic events causing or contributing to the CLL phenotype.
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| 15. |
- Alfoeldi, Jessica, et al.
(författare)
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The genome of the green anole lizard and a comparative analysis with birds and mammals
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 477:7366, s. 587-591
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments(1). Among amniotes, genome sequences are available for mammals and birds(2-4), but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes(2). Also, A. carolinensis mobile elements are very young and diverse-more so than in any other sequenced amniote genome. The GC content of this lizard genome is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds(5). We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations.
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| 16. |
- Bassil, A K, et al.
(författare)
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Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract.
- 2007
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 150:1, s. 58-64
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Obestatin, encoded by the ghrelin gene may inhibit gastrointestinal (GI) motility. This activity was re-investigated.EXPERIMENTAL APPROACH: Rat GI motility was studied in vitro (jejunum contractility and cholinergically-mediated contractions of forestomach evoked by electrical field stimulation; EFS) and in vivo (gastric emptying and intestinal myoelectrical activity). Ghrelin receptor function was studied using a GTPgammaS assay and transfected cells.KEY RESULTS: Contractions of the jejunum or forestomach were unaffected by obestatin 100 nM or 0.01-1000 nM, respectively (P>0.05 each; n=4-18). Obestatin (0.1-1 nM) reduced the ability of ghrelin 1 microM to facilitate EFS-evoked contractions of the stomach (increases were 42.7+/-7.8% and 21.2+/-5.0 % in the absence and presence of obestatin 1 nM; P<0.05; n=12); higher concentrations (10-1000 nM) tended to reduce the response to ghrelin but changes were not statistically significant. Similar concentrations of obestatin did not significantly reduce a facilitation of contractions caused by the 5-HT(4) receptor agonist prucalopride, although an inhibitory trend occurred at the higher concentrations (increases were 69.3+/-14.0% and 42.6+/-8.7% in the absence and presence of 1000 nM obestatin; n=10). Obestatin (up to 10 microM) did not modulate recombinant ghrelin receptor function. Ghrelin increased gastric emptying and reduced MMC cycle time; obestatin (1000 and 30,000 pmol kg(-1) min(-1)) had no effects. Obestatin (2500 pmol kg(-1) min(-1), starting 10 min before ghrelin) did not prevent the ability of ghrelin (500 pmol kg(-1) min(-1)) to shorten MMC cycle time.CONCLUSIONS AND IMPLICATIONS: Obestatin has little ability to modulate rat GI motility.
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| 17. |
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| 18. |
- Birnbaum, Bernard A., et al.
(författare)
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Hepatic hemangiomas: diagnosis with fusion of MR, CT, and Tc-99m-labeled red blood cell SPECT images
- 1991
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Ingår i: Radiology. - : Radiological Society of North America. - 0033-8419 .- 1527-1315. ; 181:2, s. 469-474
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Tidskriftsartikel (refereegranskat)abstract
- A method of image analysis was developed for correlation of hemangiomas detected at computed tomography {(CT)} and/or magnetic resonance {(MR)} imaging with increased blood pool activity evident at single photon emission {CT} {(SPECT)} performed after labeling of red blood cells with technetium-99m. Image analysis was performed in 20 patients with 35 known hepatic hemangiomas. After section thickness and pixel sizes of the different studies were matched, intrinsic landmarks were chosen to identify anatomically corresponding locations. Regions of interest {(ROIs)} drawn on the {CT} and/or {MR} images were translated, rotated, and reprojected to match the areas of interest on the corresponding {SPECT} images by means of a two-dimensional polynomial-based warping algorithm. Analysis of {ROIs} on 30 {SPECT-MR} and 20 {SPECT-CT} pairs of registered images provided absolute confirmation that 34 suspected hemangiomas identified on {SPECT} images correlated exactly with lesions seen on {CT} and/or {MR} images. Accuracy of fusion was within an average of 1.5 pixels +/- 0.8 (+/- 1 standard deviation). The technique enabled diagnostic confirmation of hemangiomas as small as 1.0 cm and proved useful for evaluating lesions located adjacent to intrahepatic vessels.
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| 19. |
- Broad, J, et al.
(författare)
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Changes in neuromuscular structure and functions of human colon during ageing are region-dependent
- 2019
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:7, s. 1210-1223
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Tidskriftsartikel (refereegranskat)abstract
- To determine if human colonic neuromuscular functions decline with increasing age.DesignLooking for non-specific changes in neuromuscular function, a standard burst of electrical field stimulation (EFS) was used to evoke neuronally mediated (cholinergic/nitrergic) contractions/relaxations in ex vivomuscle strips of human ascending and descending colon, aged 35–91 years (macroscopically normal tissue; 239 patients undergoing cancer resection). Then, to understand mechanisms of change, numbers and phenotype of myenteric neurons (30 306 neurons stained with different markers), densities of intramuscular nerve fibres (51 patients in total) and pathways involved in functional changes were systematically investigated (by immunohistochemistry and use of pharmacological tools) in elderly (≥70 years) and adult (35–60 years) groups.ResultsWith increasing age, EFS was more likely to evoke muscle relaxation in ascending colon instead of contraction (linear regression: n=109, slope 0.49%±0.21%/year, 95% CI), generally uninfluenced by comorbidity or use of medications. Similar changes were absent in descending colon. In the elderly, overall numbers of myenteric and neuronal nitric oxide synthase-immunoreactive neurons and intramuscular nerve densities were unchanged in ascending and descending colon, compared with adults. In elderly ascending, not descending, colon numbers of cell bodies exhibiting choline acetyltransferase immunoreactivity increased compared with adults (5.0±0.6 vs 2.4±0.3 neurons/mm myenteric plexus, p=0.04). Cholinergically mediated contractions were smaller in elderly ascending colon compared with adults (2.1±0.4 and 4.1±1.1 g-tension/g-tissue during EFS; n=25/14; p=0.04); there were no changes in nitrergic function or in ability of the muscle to contract/relax. Similar changes were absent in descending colon.ConclusionIn ascending not descending colon, ageing impairs cholinergic function.
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| 20. |
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| 21. |
- Kramer, Elissa L., et al.
(författare)
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CT-SPECT fusion to correlate radiolabeled monoclonal antibody uptake with abdominal CT findings
- 1989
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Ingår i: Radiology. - : American College of Radiology. - 0033-8419 .- 1527-1315. ; 172:3, s. 861-865
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Tidskriftsartikel (refereegranskat)abstract
- To enhance the information provided by computed tomography {(CT)} and single photon emission computed tomography {(SPECT)} performed with radiolabeled, anti-carcinoembryonic antigen monoclonal antibody {(MoAb)}, the authors performed fusion of these types of images from eight subjects with suspected colorectal adenocarcinoma. Section thickness and pixel size of the two studies were matched, coordinates of corresponding points from each study were identified, and {CT} sections were translated, rotated, and reprojected to match the corresponding {SPECT} scans. The {CT-SPECT} fusion enabled identification of anatomic sites of tumor-specific {MoAb} accumulation in four cases, showed non-specific {MoAb} accumulation in two, and helped confirm information only suggested by the two studies separately in one.
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| 22. |
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| 23. |
- Moczek, Armin P., et al.
(författare)
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The significance and scope of evolutionary developmental biology : a vision for the 21st century
- 2015
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Ingår i: Evolution & development. ; 17:3, s. 198-219
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Tidskriftsartikel (refereegranskat)abstract
- Evolutionary developmental biology (evo-devo) has undergone dramatic transformations since its emergence as a distinct discipline. This paper aims to highlight the scope, power, and future promise of evo-devo to transform and unify diverse aspects of biology. We articulate key questions at the core of eleven biological disciplines-from Evolution, Development, Paleontology, and Neurobiology to Cellular and Molecular Biology, Quantitative Genetics, Human Diseases, Ecology, Agriculture and Science Education, and lastly, Evolutionary Developmental Biology itself-and discuss why evo-devo is uniquely situated to substantially improve our ability to find meaningful answers to these fundamental questions. We posit that the tools, concepts, and ways of thinking developed by evo-devo have profound potential to advance, integrate, and unify biological sciences as well as inform policy decisions and illuminate science education. We look to the next generation of evolutionary developmental biologists to help shape this process as we confront the scientific challenges of the 21st century.
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| 24. |
- Noz, Marilyn E., et al.
(författare)
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An integrated approach to biodistribution radiation absorbed dose estimates
- 1993
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Ingår i: European Journal of Nuclear Medicine. - 0340-6997 .- 1432-105X. ; 20:2, s. 165-169
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Tidskriftsartikel (refereegranskat)abstract
- An integrated approach to existing methods of extracting biodistribution data, pharmacokinetics and radiation absorbed dose estimates from serial scintigraphic images is described. This approach employs a single computer-generated user interface to reformat planar scans into a standard file type, align conjugate (anterior and posterior) images, draw regions of interest {(ROIs)} over selected organs and lesions and generate count data for anterior and posterior views and calculated geometric means. Using standard correction methods, the fraction injected activity is obtained for all {ROIs} and total body. This methodology has been applied to the analysis of {indium-III-labelled} breast-cancer-directed antibodies and technetium-90m-labelled {CEA-specific} antibody fragments in non-small-cell lung cancer. It is anticipated that this approach will be useful for evaluating the dosimetry of other radiolabelled monoclonal antibodies, as well as other radiopharmaceuticals.}
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| 25. |
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| 26. |
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| 27. |
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| 28. |
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| 29. |
- Hellström, Per M., et al.
(författare)
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The pharmacodynamics, safety and pharmacokinetics of single doses of the motilin agonist, camicinal, in type 1 diabetes mellitus with slow gastric emptying
- 2016
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 173:11, s. 1768-1777
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE Here we have investigated the pharmacokinetics, pharmacodynamics and safety of single doses of camicinal in type 1 diabetes mellitus (T1DM) patients with a history of slow gastric emptying with symptoms consistent with gastroparesis. EXPERIMENTAL APPROACH In a randomized, double-blind, placebo-controlled, incomplete block, three-period, two-centre crossover study, patients received oral administration of placebo and two of the three possible doses of camicinal (25, 50 or 125 mg). Gastric emptying (C-13-octanoic acid breath test), pharmacokinetics and safety were primary outcomes. KEY RESULTS Nine of the 10 patients enrolled completed the study. Gastric half-emptying time decreased by -95 min (95% CI: -156.8, -34.2) after a single dose of camicinal 125 mg compared with placebo (52 vs. 147 min, P < 0.05), representing a 65% improvement. A decrease of the gastric half-emptying time compared with placebo (approximately 39 min) was observed with camicinal 25 and 50 mg, representing a 27% reduction for both doses (not statistically significant). A positive exposure-response relationship was demonstrated across all doses. The effects of camicinal on gastric half-emptying time were not influenced by fasting glucose levels. Single doses up to 125 mg were well tolerated. Camicinal was well absorbed, exhibiting linear and approximately dose-proportional pharmacokinetic characteristics and a clear exposure-response relationship with gastric emptying. CONCLUSIONS AND IMPLICATIONS Camicinal significantly accelerated gastric emptying of solids in T1DM patients following administration of a single oral dose. Camicinal was well tolerated and exhibited similar pharmacokinetic characteristics in diabetic patients to those previously reported in healthy volunteers.
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| 30. |
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| 31. |
- Kramer, Elissa L., et al.
(författare)
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Fusing of immunoscintigraphy SPECT with CT or MRI for improved multimodality image interpretation
- 1992
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Ingår i: Engineering in Medicine and Biology Society, 1992 14th Annual International Conference of the IEEE. - : IEEE. - 0780307852 ; , s. 1805-1806
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Konferensbidrag (refereegranskat)abstract
- Correlation of PET or SPECT functional with CT or MRI anatomic transaxial images often enhances the information available on these studies. Careful registraÂtion of images from two types of studies may be used to identify a structure containing to a PET or SPECT abnormality or to evaluate the functional or metabolic characteristics of an abnormal or normal structure. CTSPECT or PET image registration has been applied to brain imaging for metabolic and cerebral perfusion studies [1–3], more recently, to Ga-67 imaging of the chest [4], as well as to CT-SPECT correlation in cancer patients undergoing immunoscintigraphy [5–7]. We have applied an image registration technique to correlate CT or MRI of the abdomen and chest with SPECT images obtained after the administration of tumor-directed radiolabeled monoclonal antibodies. Correlation of PET or SPECT functional with CT or MRI anatomic transaxial images often enhances the information available on these studies. Careful registration of images from two types of studies may be used to identify a structure containing to a PET or SPECT abnormality or to evaluate the functional or metabolic characteristics of an attempt to improve our interpretation of these imaging studies.
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| 32. |
- Maguire Jr., Gerald Q., et al.
(författare)
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Graphics applied to medical image registration
- 1991
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Ingår i: IEEE Computer Graphics and Applications. - : IEEE. - 0272-1716 .- 1558-1756. ; 11:2, s. 20-27
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Tidskriftsartikel (refereegranskat)abstract
- Software that has been developed to automate and standardize comparison of 3D images is discussed. The major approaches to image registration are examined. The authors' registration and reconstruction software is described. Studies carried out to determine the relative accuracy of the present registration methods are reported. The main goal of the authors is to improve on commercial SPECT reconstruction algorithms and provide quantification accuracy sufficient for numerical assessment of tracer distribution.
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| 33. |
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Olsson, Catharina, 1968, et al.
(författare)
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Identification of genes for the ghrelin and motilin receptors and a novel related gene in fish, and stimulation of intestinal motility in zebrafish (Danio rerio) by ghrelin and motilin.
- 2008
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Ingår i: General and comparative endocrinology. - : Elsevier BV. - 0016-6480. ; 155:1, s. 217-26
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Tidskriftsartikel (refereegranskat)abstract
- In mammals ghrelin has a diverse range of effects including stimulation of gut motility but although present in teleost fish its effects on motility have not been investigated. The present study used bioinformatics to search for fish paralogues of the ghrelin receptor and the closely related motilin receptor, and investigated the effects of ghrelin and motilin on gut motility in zebrafish, Danio rerio. Fish paralogues of the human ghrelin and motilin receptor genes were identified, including those from the zebrafish. In addition, a third gene was identified in three species of pufferfish (the only fish genome completely sequenced), which is distinct from the ghrelin and motilin receptors but more closely aligned to these receptors relative to other G-protein coupled receptors. Immunohistochemistry demonstrated strong ghrelin receptor-like reactivity in the muscle of the zebrafish intestine. In isolated intestinal bulb and mid/distal intestine preparations, ghrelin, motilin, and the motilin receptor agonist erythromycin all evoked contraction; these responses ranged between 9% and 51% of the contractions evoked by carbachol (10(-6) M). There were some variations in the concentrations found to be active in the different tissues, e.g., whereas motilin and rat ghrelin caused contraction of the intestinal bulb circular muscle at concentrations as low as 10(-8) M, human ghrelin (10(-8) to 10(-6) M) was without activity. Neither ghrelin (10(-7) M) nor erythromycin (10(-5) M) affected the contractions evoked by electrical field stimulation. The results suggest that both ghrelin and motilin can regulate intestinal motility in zebrafish and most likely other teleosts, and are discussed in relation to the evolution of these regulatory peptides.
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| 38. |
- Sanger, G J, et al.
(författare)
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GSK962040 : a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility
- 2009
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 21:6, s. 657-664, e30-31
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent clinical need for a safe, efficacious stimulant of gastric emptying; current therapies include erythromycin (an antibiotic with additional properties which preclude chronic use) and metoclopramide (a 5-hydroxytryptamine type 4 receptor agonist and an antagonist at brain D2 receptors, associated with movement disorders). To move away from the complex motilide structure of erythromycin, a small molecule motilin receptor agonist, GSK962040, was identified and characterized. The compound was evaluated using recombinant human receptors, rabbit and human isolated stomach preparations known to respond to motilin and in vivo, by measuring its ability to increase defecation in conscious rabbits. At the human motilin receptor, the pEC50 (the negative logarithm to base 10 of the EC50 value, the concentration of agonist that produces 50% of the maximal response) values for GSK962040 and erythromycin as agonists were, respectively, 7.9 and 7.3; GSK962040 had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, GSK962040 300 nmol L−1–10 μmol L−1 caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 ± 47% at 3 μmol L−1. In human-isolated stomach, GSK962040 10 μmol L−1, erythromycin 10 μmol L−1 and [Nle13]-motilin 100 nmol L−1, each caused muscle contraction of similar amplitude. In conscious rabbits, intravenous doses of 5 mg kg−1 GSK962040 or 10 mg kg−1 erythromycin significantly increased faecal output over a 2-h period. Together, these data show that GSK962040, a non-motilide structure, selectively activates the motilin receptor. Simplification of the structural requirements to activate this receptor greatly facilitates the design of potentially new medicines for gastroparesis.
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| 39. |
- Sanger, Gareth J, et al.
(författare)
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The hungry stomach : Physiology, disease, and drug development opportunities
- 2010
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Ingår i: Frontiers in pharmacology. - : Frontiers Media SA. - 1663-9812. ; 1, s. 145-
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Tidskriftsartikel (refereegranskat)abstract
- During hunger, a series of high-amplitude contractions of the stomach and small intestine (phase III), which form part of a cycle of quiescence and contractions (known as the migrating motor complex, MMC), play a "housekeeping" role prior to the next meal, and may contribute toward the development of hunger. Several gastrointestinal (GI) hormones are associated with phase III MMC activity, but currently the most prominent is motilin, thought to at least partly mediate phase III contractions of the gastric MMC. Additional GI endocrine and neuronal systems play even more powerful roles in the development of hunger. In particular, the ghrelin-precursor gene is proving to have a complex physiology, giving rise to three different products: ghrelin itself, which is formed from a post-translational modification of des-acyl-ghrelin, and obestatin. The receptors acted on by des-acyl-ghrelin and by obestatin are currently unknown but both these peptides seem able to exert actions which oppose that of ghrelin, either indirectly or directly. An increased understanding of the actions of these peptides is helping to unravel a number of different eating disorders and providing opportunities for the discovery of new drugs to regulate dysfunctional gastric behaviors and appetite. To date, ghrelin and motilin receptor agonists and antagonists have been described. The most advanced are compounds which activate the ghrelin and motilin receptors which are being progressed for disorders associated with gastric hypomotility.
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| 41. |
- Webb, Dominic-Luc, et al.
(författare)
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The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression
- 2013
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Ingår i: Naunyn-Schmiedeberg's Archives of Pharmacology. - : Springer Verlag (Germany). - 0028-1298 .- 1432-1912. ; 386:1, s. 41-49
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Tidskriftsartikel (refereegranskat)abstract
- YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were followed by diclofenac. Four hours later, gastric tissue was excised and analyzed for ulcer index. An intragastrically implanted Bravo capsule measured pH for 5 days during YF476 plus pentagastrin treatment. Changes in gene expression were assayed for gastrin, ghrelin, and somatostatin; their receptors; and iNOS. YF476 acutely (within 4 h) protected against diclofenac-induced gastric ulcers equivalent to esomeprazole. Gastric pH recorded during 5 days in the presence of pentagastrin was 1.83 (+/- 0.06). YF476 raised pH to 3.67 (+/- 0.09) and plasma ghrelin, gastrin, and somatostatin increased. YF476 increased gene expression of somatostatin receptor and gastrin, while ghrelin receptor decreased; transcripts coding ghrelin, somatostatin, and CCK-2R remained unchanged. In the presence of diclofenac, esomeprazole increased expression of all these transcripts and that of iNOS, while YF476 yielded only decreased CCK-2R and increased iNOS transcripts. YF476 is a potential new preventative treatment for patients at risk of nonsteroidal antiinflammatory drug (NSAID)-induced ulceration. Gastric gene expressions of ghrelin, gastrin, and somatostatin and their receptors differ between esomeprazole and YF476. Despite these differences and different modes of action to raise gastric pH, both drugs acutely increase iNOS, suggesting iNOS expression parallels pH.
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