Search

Your search keyword '"Macphee, Colin H."' showing total 174 results
Start Over Author "Macphee, Colin H."
174 results on '"Macphee, Colin H."'

2. Pharmacological blockade of the mast cell MRGPRX2 receptor supports investigation of its relevance in skin disorders.

Author

Macphee, Colin H., Xinzhong Dong, Qi Peng, Paone, Daniel V., Skov, Per Stahl, Baumann, Katrine, Roethke, Theresa, Goldspink, Deborah A., Pearson, Samuel K., and Zining Wu

Subjects
MAST cells, SUBSTANCE P, CELL receptors, SKIN care products, GHRELIN receptors
Abstract

Introduction: Because MRGPRX2 is now recognized as the mast cell receptor for basic secretagogues, there is currently a tremendous interest in whetherMRGRPX2 could play an important role in various pruritic dermatoses such as chronic spontaneous urticaria. Therefore, we sought to identify new potent and selective antagonists to pharmacologically characterize the biological role of MRGPRX2. Methods: Various relevant in vitro, ex vivo, and in vivo model systems were used to investigate the role of MRGPRX2. This included the study of freshly isolated human skin mast cells and human basophils as well as an ex vivo human skin microdialysis preparation. The additivity of MRGPRX2 and FceR1-mediated degranulation was also investigated. Human MRGPRX2 knock-in mice were generated to interrogate pharmacokinetic/pharmacodynamic relationships because both antagonists studied were shown to be human specific. Results: Two novel and structurally distinct MRGPRX2 antagonists were identified with one, Compound B, being orally active and demonstrating high potency in blocking Substance P-mediated degranulation using freshly isolated human skin mast cells with half maximal inhibitory concentration (IC50) at 0.42 nM. Compound B also potently blocked Substance P-stimulated histamine release from resident mast cells in a human skin explant setup as well as blocking itch in an established behavioral scratching model using MRGPRX2 knock-in mice. Unlike human mast cells, Substance P failed to elicit a functional response in human basophils. Conclusion: These data fully support the investigation of MRGPRX2 receptor antagonists in mast cell-driven allergic skin disorders such as chronic spontaneous urticaria. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

6. Diabetes status modifies the long-term effect of lipoprotein-associated phospholipase A2 on major coronary events.

Author

Siddiqui, Moneeza K, Smith, Gillian, St Jean, Pamela, Dawed, Adem Y, Bell, Samira, Soto-Pedre, Enrique, Kennedy, Gwen, Carr, Fiona, Wallentin, Lars, White, Harvey, Macphee, Colin H, Waterworth, Dawn, Palmer, Colin N A, Siddiqui, Moneeza K, Smith, Gillian, St Jean, Pamela, Dawed, Adem Y, Bell, Samira, Soto-Pedre, Enrique, Kennedy, Gwen, Carr, Fiona, Wallentin, Lars, White, Harvey, Macphee, Colin H, Waterworth, Dawn, and Palmer, Colin N A

Abstract

AIMS/HYPOTHESIS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has an independent prognostic association with major coronary events (MCE). However, no study has investigated whether type 2 diabetes status modifies the effect of Lp-PLA2 activity or inhibition on the risk of MCE. We investigate the interaction between diabetes status and Lp-PLA2 activity with risk of MCE. Subsequently, we test the resulting hypothesis that diabetes status will play a role in modifying the efficacy of an Lp-PLA2 inhibitor. METHODS: A retrospective cohort study design was utilised in two study populations. Discovery analyses were performed in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort based in Scotland, UK. Participants were categorised by type 2 diabetes control status: poorly controlled (HbA1c ≥ 48 mmol/mol or ≥6.5%) and well-controlled (HbA1c < 48 mmol/mol or <6.5%) diabetes (n = 7420). In a secondary analysis of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial of Lp-PLA2 inhibitor (darapladib) efficacy, 15,828 participants were stratified post hoc by type 2 diabetes diagnosis status (diabetes or no diabetes) at time of recruitment. Lp-PLA2 activity was then divided into population-specific quartiles. MCE were determined from linked medical records in GoDARTS and trial records in STABILITY. First, the interaction between diabetes control status and Lp-PLA2 activity on the outcome of MCE was explored in GoDARTS. The effect was replicated in the placebo arm of STABILITY. The effect of Lp-PLA2 on MCE was then examined in models stratified by diabetes status. This helped determine participants at higher risk. Finally, the effect of Lp-PLA2 inhibition was assessed in STABILITY in the higher risk group. Cox proportional hazards models adjusted for confounders were used to assess associations. RESULTS: In GoDARTS, a significant interaction between increased Lp-PLA2 activity (continuous

Published
2022
Full Text
View/download PDF

9. Diabetes status modifies the long-term effect of lipoprotein-associated phospholipase A2 on major coronary events

Author

Siddiqui, Moneeza K., primary, Smith, Gillian, additional, St Jean, Pamela, additional, Dawed, Adem Y., additional, Bell, Samira, additional, Soto-Pedre, Enrique, additional, Kennedy, Gwen, additional, Carr, Fiona, additional, Wallentin, Lars, additional, White, Harvey, additional, Macphee, Colin H., additional, Waterworth, Dawn, additional, and Palmer, Colin N. A., additional

Published
2021
Full Text
View/download PDF

10. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development

Author

Wilensky, Robert L, Shi, Yi, Mohler, III, Emile R, Hamamdzic, Damir, Burgert, Mark E, Li, Jun, Postle, Anthony, Fenning, Robert S, Bollinger, James G, Hoffman, Bryan E, Pelchovitz, Daniel J, Yang, Jisheng, Mirabile, Rosanna C, Webb, Christine L, Zhang, LeFeng, Zhang, Ping, Gelb, Michael H, Walker, Max C, Zalewski, Andrew, and Macphee, Colin H

Published
2008
Full Text
View/download PDF

13. Lipoprotein-associated phospholipase A(sub 2) as an independent predictor of coronary heart disease

Author

Packard, Chris J., O'Reilly, Denis S.J., Caslake, Muriel J., McMahon, Alex D., Ford, Ian, Cooney, Josephine, Macphee, Colin H., Suckling, Keith E., Krishna, Mala, Wilkinson, Francis E., Rumley, Ann, and Lowe, Gordon D.O.

Subjects
Phospholipases -- Health aspects, Coronary heart disease -- Patient outcomes, Heart attack -- Risk factors
Abstract

Elevated blood levels of lipoprotein-associated phospholipase A(sub 2) may predict which men will have a heart attack or die from coronary artery disease. This enzyme may modify low-density lipoproteins inside coronary arteries.

Published
2000

25. Retinal pathology is associated with increased blood–retina barrier permeability in a diabetic and hypercholesterolaemic pig model: Beneficial effects of the LpPLA2 inhibitor Darapladib

Author

Acharya, Nimish K, primary, Qi, Xin, additional, Goldwaser, Eric L, additional, Godsey, George A, additional, Wu, Hao, additional, Kosciuk, Mary C, additional, Freeman, Theresa A, additional, Macphee, Colin H, additional, Wilensky, Robert L, additional, Venkataraman, Venkat, additional, and Nagele, Robert G, additional

Published
2017
Full Text
View/download PDF

26. Specificity of Lipoprotein-Associated Phospholipase A2 Towards Oxidized Phosphatidylserines: LC-ESI-MS Characterization of Products and Computer Modeling of Interactions

Author

Tyurin, Vladimir A., Yanamala, Naveena, Tyurina, Yulia Y., Klein-Seetharaman, Judith, Macphee, Colin H., and Kagan, Valerian E.

Subjects
Molecular Docking Simulation, Spectrometry, Mass, Electrospray Ionization, 1-Alkyl-2-acetylglycerophosphocholine Esterase, lipids (amino acids, peptides, and proteins), Computer Simulation, Phosphatidylserines, Article, Chromatography, Liquid
Abstract

Ca(2+)-independent lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a member of the phospholipase A(2) superfamily with a distinguishing characteristic of high specificity for oxidatively modified sn-2 fatty acid residues in phospholipids that has been especially well characterized for peroxidized species of phosphatidylcholines (PC). The ability of Lp-PLA(2) to hydrolyze peroxidized species of phosphatidylserine (PS), acting as a recognition signal for clearance of apoptotic cells by professional phagocytes, as well as the products of the reaction has not been investigated. We performed liquid chromatography-electrospray ionization mass spectrometry-based structural characterization of oxygenated, hydrolyzed molecular species of PS-containing linoleic acid in either the sn-2 position (C(18:0)/C(18:2)) or in both sn-1 and sn-2 positions (C(18:2)/C(18:2)), formed in the cytochrome c- and H(2)O(2)-driven enzymatic oxidation reaction. Cytochrome c has been chosen as a catalyst of peroxidation reactions because of its likely involvement in PS oxidation in apoptotic cells. We found that Lp-PLA(2) catalyzed the hydrolysis of both nontruncated and truncated (oxidatively fragmented) species of oxidized PS species, albeit with different efficiencies, and performed detailed characterization of the major reaction products: oxygenated derivatives of linoleic acid as well as nonoxygenated and oxygenated species of lyso-PS. Among linoleic acid products, derivatives oxygenated at the C(9) position, including 9-hydroxyoctadecadienoic acid (9-HODE), a potent ligand of G protein-coupled receptor G2A, were the most abundant. Computer modeling of interactions of Lp-PLA(2) with different PS-oxidized species indicated that they are able to bind in the proximity (5 Å) of Ser273 and His351 of the catalytic triad. For 9-hydroxy and 9-hydroperoxy derivatives of oxidized PS, the sn-2 ester bond was positioned very close (3 Å) to the Ser273 residue, a nucleophile directly attacking the sn-2 bond, thus favoring the hydrolysis reaction. We suggest that oxidatively modified free fatty acids and lyso-PS species generated by Lp-PLA(2) may represent important signals facilitating and regulating the execution of apoptotic and phagocytosis programs essential for the control of inflammation.

Published
2012

27. Atherosclerotic Plaque Inflammation Varies Between Vascular Sites and Correlates With Response to Inhibition of Lipoprotein‐Associated Phospholipase A 2

Author

Fenning, Robert S., primary, Burgert, Mark E., additional, Hamamdzic, Damir, additional, Peyster, Eliot G., additional, Mohler, Emile R., additional, Kangovi, Shreya, additional, Jucker, Beat M., additional, Lenhard, Stephen C., additional, Macphee, Colin H., additional, and Wilensky, Robert L., additional

Published
2015
Full Text
View/download PDF

28. Retinal pathology is associated with increased blood–retina barrier permeability in a diabetic and hypercholesterolaemic pig model: Beneficial effects of the LpPLA2 inhibitor Darapladib.

Author

Acharya, Nimish K., Qi, Xin, Goldwaser, Eric L., Godsey, George A., Wu, Hao, Kosciuk, Mary C., Freeman, Theresa A., Macphee, Colin H., Wilensky, Robert L., Venkataraman, Venkat, and Nagele, Robert G.

Abstract

Using a porcine model of diabetes mellitus and hypercholesterolaemia, we previously showed that diabetes mellitus and hypercholesterolaemia is associated with a chronic increase in blood–brain barrier permeability in the cerebral cortex, leading to selective binding of immunoglobulin G and deposition of amyloid-beta1-42 peptide in pyramidal neurons. Treatment with Darapladib (GlaxoSmithKline, SB480848), an inhibitor of lipoprotein-associated phospholipase-A2, alleviated these effects. Here, investigation of the effects of chronic diabetes mellitus and hypercholesterolaemia on the pig retina revealed a corresponding increased permeability of the blood–retina barrier coupled with a leak of plasma components into the retina, alterations in retinal architecture, selective IgG binding to neurons in the ganglion cell layer, thinning of retinal layers due to cell loss and increased glial fibrillary acidic protein expression in Müller cells, all of which were curtailed by treatment with Darapladib. These findings suggest that chronic diabetes mellitus and hypercholesterolaemia induces increased blood–retina barrier permeability that may be linked to altered expression of blood–retina barrier–associated tight junction proteins, claudin and occludin, leading to structural changes in the retina consistent with diabetic retinopathy. Additionally, results suggest that drugs with vascular anti-inflammatory properties, such as Darapladib, may have beneficial effects on eye diseases strongly linked to vascular abnormalities such as diabetic retinopathy and age-related macular degeneration. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
View/download PDF

31. Diabetes and Hypercholesterolemia Increase Blood-Brain Barrier Permeability and Brain Amyloid Deposition: Beneficial Effects of the LpPLA2 Inhibitor Darapladib

Author

Acharya, Nimish K., primary, Levin, Eli C., additional, Clifford, Peter M., additional, Han, Min, additional, Tourtellotte, Ryan, additional, Chamberlain, Dean, additional, Pollaro, Michael, additional, Coretti, Nicholas J., additional, Kosciuk, Mary C., additional, Nagele, Eric P., additional, DeMarshall, Cassandra, additional, Freeman, Theresa, additional, Shi, Yi, additional, Guan, Chenbing, additional, Macphee, Colin H., additional, Wilensky, Robert L., additional, and Nagele, Robert G., additional

Published
2013
Full Text
View/download PDF

35. Pharmacological Inhibition of C-C Chemokine Receptor 2 Decreases Macrophage Infiltration in the Aortic Root of the Human C-C Chemokine Receptor 2/Apolipoprotein E −/− Mouse: Magnetic Resonance Imaging Assessment

Author

Olzinski, Alan R., primary, Turner, Gregory H., additional, Bernard, Roberta E., additional, Karr, Heather, additional, Cornejo, Carla A., additional, Aravindhan, Karpagam, additional, Hoang, Bao, additional, Ringenberg, Michael A., additional, Qin, Pu, additional, Goodman, Krista B., additional, Willette, Robert N., additional, Macphee, Colin H., additional, Jucker, Beat M., additional, Sehon, Clark A., additional, and Gough, Peter J., additional

Published
2010
Full Text
View/download PDF

37. Electrospray Ionization Mass Spectrometry Identifies Substrates and Products of Lipoprotein-associated Phospholipase A2 in Oxidized Human Low Density Lipoprotein

Author

Davis, Bill, primary, Koster, Grielof, additional, Douet, Lisa J., additional, Scigelova, Michaela, additional, Woffendin, Gary, additional, Ward, Joanna M., additional, Smith, Alberto, additional, Humphries, Julia, additional, Burnand, Kevin G., additional, Macphee, Colin H., additional, and Postle, Anthony D., additional

Published
2008
Full Text
View/download PDF

41. Synthetic LXR agonists increase LDL in CETP species

Author

Groot, Pieter H.E., primary, Pearce, Nigel J., additional, Yates, John W., additional, Stocker, Claire, additional, Sauermelch, Charles, additional, Doe, Christopher P., additional, Willette, Robert N., additional, Olzinski, Alan, additional, Peters, Tambra, additional, d'Epagnier, Denise, additional, Morasco, Kathleen O., additional, Krawiec, John A., additional, Webb, Christine L., additional, Aravindhan, Karpagam, additional, Jucker, Beat, additional, Burgert, Mark, additional, Ma, Chun, additional, Marino, Joseph P., additional, Collins, Jon L., additional, Macphee, Colin H., additional, Thompson, Scott K., additional, and Jaye, Michael, additional

Published
2005
Full Text
View/download PDF

43. Discovery of Substituted Maleimides as Liver X Receptor Agonists and Determination of a Ligand-Bound Crystal Structure

Author

Jaye, Michael C., primary, Krawiec, John A., additional, Campobasso, Nino, additional, Smallwood, Angela, additional, Qiu, Chunyan, additional, Lu, Quinn, additional, Kerrigan, John J., additional, De Los Frailes Alvaro, Maite, additional, Laffitte, Bryan, additional, Liu, Wu-Schyong, additional, Marino,, Joseph P., additional, Meyer, Craig R., additional, Nichols, Jason A., additional, Parks, Derek J., additional, Perez, Paloma, additional, Sarov-Blat, Lea, additional, Seepersaud, Sheila D., additional, Steplewski, Klaudia M., additional, Thompson, Scott K., additional, Wang, Ping, additional, Watson, Mike A., additional, Webb, Christine L., additional, Haigh, David, additional, Caravella, Justin A., additional, Macphee, Colin H., additional, Willson, Timothy M., additional, and Collins, Jon L., additional

Published
2005
Full Text
View/download PDF

45. The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2

Author

Blackie, Josie A., primary, Bloomer, Jackie C., additional, Brown, Murray J.B., additional, Cheng, Hung-Yuan, additional, Hammond, Beverley, additional, Hickey, Deirdre M.B., additional, Ife, Robert J., additional, Leach, Colin A., additional, Lewis, V.Ann, additional, Macphee, Colin H., additional, Milliner, Kevin J., additional, Moores, Kitty E., additional, Pinto, Ivan L., additional, Smith, Stephen A., additional, Stansfield, Ian G., additional, Stanway, Steven J., additional, Taylor, Maxine A., additional, and Theobald, Colin J., additional

Published
2003
Full Text
View/download PDF

47. The discovery of SB-435495

Author

Blackie, Josie A., primary, Bloomer, Jackie C., additional, Brown, Murray J.B., additional, Cheng, Hung-Yuan, additional, Elliott, Richard L., additional, Hammond, Beverley, additional, Hickey, Deirdre M.B., additional, Ife, Robert J., additional, Leach, Colin A., additional, Lewis, V.Ann, additional, Macphee, Colin H., additional, Milliner, Kevin J., additional, Moores, Kitty E., additional, Pinto, Ivan L., additional, Smith, Stephen A., additional, Stansfield, Ian G., additional, Stanway, Steven J., additional, Taylor, Maxine A., additional, Theobald, Colin J., additional, and Whittaker, Caroline M., additional

Published
2002
Full Text
View/download PDF

50. Potent, orally active inhibitors of lipoprotein-associated phospholipase A2: 1-(biphenylmethylamidoalkyl)-pyrimidones

Author

Boyd, Helen F., primary, Fell, Stephen C.M., additional, Hickey, Deirdre M.B., additional, Ife, Robert J., additional, Leach, Colin A., additional, Macphee, Colin H., additional, Milliner, Kevin J., additional, Pinto, Ivan L., additional, Rawlings, D.Anthony, additional, Smith, Stephen A., additional, Stansfield, Ian G., additional, Stanway, Steven J., additional, Theobald, Colin J., additional, and Whittaker, Caroline M., additional

Published
2002
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results