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466 results on '"Iredale, John P."'

1. Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis

Author

Hayes, Alastair J., Zheng, Xiaozhong, O’Kelly, James, Neyton, Lucile P.A., Bochkina, Natalia A., Uings, Iain, Liddle, John, Baillie, J. Kenneth, Just, George, Binnie, Margaret, Homer, Natalie Z.M., Murray, Toby B.J., Baily, James, McGuire, Kris, Skouras, Christos, Garden, O. James, Webster, Scott P., Iredale, John P., Howie, Sarah E.M., and Mole, Damian J.

Published
2023
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2. In utero exposures to perfluoroalkyl substances and the human fetal liver metabolome in Scotland : a cross-sectional study

Author

Hyötyläinen, Tuulia, McGlinchey, Aidan J, Salihovic, Samira, Schubert, Antonia, Douglas, Alex, Hay, David C., O'Shaughnessy, Peter J., Iredale, John P., Shaw, Sophie, Fowler, Paul A., Oresic, Matej, Hyötyläinen, Tuulia, McGlinchey, Aidan J, Salihovic, Samira, Schubert, Antonia, Douglas, Alex, Hay, David C., O'Shaughnessy, Peter J., Iredale, John P., Shaw, Sophie, Fowler, Paul A., and Oresic, Matej

Abstract

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances are classed as endocrine disrupting compounds but continue to be used in many products such as firefighting foams, flame retardants, utensil coatings, and waterproofing of food packaging. Perfluoroalkyl exposure aberrantly modulates lipid, metabolite, and bile acid levels, increasing susceptibility to onset and severity of metabolic diseases, such as diabetes and metabolic dysfunction-associated steatotic liver disease. To date, most studies in humans have focused on perfluoroalkyl-exposure effects in adults. In this study we aimed to show if perfluoroalkyls are present in the human fetal liver and if they have metabolic consequences for the human fetus. METHODS: In this cross-sectional study, human fetal livers from elective termination of pregnancies at the Aberdeen Pregnancy Counselling Service, Aberdeen, UK, were analysed by both targeted (bile acids and perfluoroalkyl substances) and combined targeted and untargeted (lipids and polar metabolites) mass spectrometry based metabolomic analyses, as well as with RNA-Seq. Only fetuses from normally progressing pregnancies (determined at ultrasound scan before termination), terminated for non-medical reasons, from women older than 16 years, fluent in English, and between 11 and 21 weeks of gestation were collected. Women exhibiting considerable emotional distress or whose fetuses had anomalies identified at ultrasound scan were excluded. Stringent bioinformatic and statistical methods such as partial correlation network analysis, linear regression, and pathway analysis were applied to this data to investigate the association of perfluoroalkyl exposure with hepatic metabolic pathways. FINDINGS: Fetuses included in this study were collected between Dec 2, 2004, and Oct 27, 2014. 78 fetuses were included in the study: all 78 fetuses were included in the metabolomics analysis (40 female and 38 male) and 57 fetuses were included in the RNA-Seq analysis (28 female an, FUNDING: UK Medical Research Council, Horizon Europe Program of the European Union, Seventh Framework Programme of the European Union, NHS Grampian Endowments grants, European Partnership for the Assessment of Risks from Chemicals, Swedish Research Council, Formas, Novo Nordisk Foundation, and the Academy of Finland.

Published
2024
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3. In utero exposures to perfluoroalkyl substances and the human fetal liver metabolome in Scotland: a cross-sectional study

Author

Hyötyläinen, Tuulia, primary, McGlinchey, Aidan, additional, Salihovic, Samira, additional, Schubert, Antonia, additional, Douglas, Alex, additional, Hay, David C, additional, O'Shaughnessy, Peter J, additional, Iredale, John P, additional, Shaw, Sophie, additional, Fowler, Paul A, additional, and Orešič, Matej, additional

Published
2024
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5. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs

Author

Henderson, Neil C, Arnold, Thomas D, Katamura, Yoshio, Giacomini, Marilyn M, Rodriguez, Juan D, McCarty, Joseph H, Pellicoro, Antonella, Raschperger, Elisabeth, Betsholtz, Christer, Ruminski, Peter G, Griggs, David W, Prinsen, Michael J, Maher, Jacquelyn J, Iredale, John P, Lacy-Hulbert, Adam, Adams, Ralf H, and Sheppard, Dean

Subjects
Biomedical and Clinical Sciences, Health Sciences, Genetics, Animals, Cells, Cultured, Drug Evaluation, Preclinical, Female, Fibrosis, Gene Targeting, Integrin alphaV, Kidney, Kidney Diseases, Liver Cirrhosis, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myofibroblasts, Pulmonary Fibrosis, Signal Transduction, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.

Published
2013

8. CCR Translation on this Article from The Desmoplastic Reaction Surrounding Hepatic Colorectal Adenocarcinoma Metastases Aids Tumor Growth and Survival via αv Integrin Ligation

Author

Conti, John A., primary, Kendall, Timothy J., primary, Bateman, Adrian, primary, Armstrong, Thomas A., primary, Papa-Adams, Andrew, primary, Xu, Qian, primary, Packham, Graham, primary, Primrose, John N., primary, Benyon, R. Christopher, primary, and Iredale, John P., primary

Published
2023
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10. Prostaglandin E₂ constrains systemic inflammation through an innate lymphoid cell-IL-22 axis

Author

Duffin, Rodger, O'Connor, Richard A., Crittenden, Siobhan, Forster, Thorsten, Yu, Cunjing, Zheng, Xiaozhong, Smyth, Danielle, Robb, Calum T., Rossi, Fiona, Skouras, Christos, Tang, Shaohui, Richards, James, Pellicoro, Antonella, Weller, Richard B., Breyer, Richard M., Mole, Damian J., Iredale, John P., Anderton, Stephen M., Narumiya, Shuh, Maizels, Rick M., Ghazal, Peter, Howie, Sarah E., Rossi, Adriano G., and Yao, Chengcan

Published
2016

15. Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

Author

Mole, Damian J., Webster, Scott P., Uings, Iain, Zheng, Xiaozhong, Binnie, Margaret, Wilson, Kris, Hutchinson, Jonathan P., Mirguet, Olivier, Walker, Ann, Beaufils, Benjamin, Ancellin, Nicolas, Trottet, Lionel, Beneton, Veronique, Mowat, Christopher G., Wilkinson, Martin, Rowland, Paul, Haslam, Carl, McBride, Andrew, Homer, Natalie Z.M., Baily, James E., Sharp, Matthew G.F., Garden, O. James, Hughes, Jeremy, Howie, Sarah E.M., Holmes, Duncan S., Liddle, John, and Iredale, John P.

Subjects
Multiple organ failure -- Genetic aspects -- Prevention, Enzymes -- Regulation, Pancreatitis -- Genetic aspects -- Development and progression, Oxidases -- Health aspects, Biological sciences, Health
Abstract

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death (1,2). Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population (4). There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism (5), is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 A resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness., Systemic tryptophan metabolism in mammals occurs primarily via the kynurenine pathway (Fig. 1a) (5). Tryptophan metabolites contribute to acute lung injury in rats with [AP.sup.6], and the tryptophan metabolite kynurenine [...]

Published
2016

19. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

Author

Ramachandran, Prakash, Pellicoro, Antonella, Vernon, Madeleine A., Boulter, Luke, Aucott, Rebecca L., Ali, Aysha, Hartland, Stephen N., Snowdon, Victoria K., Cappon, Andrea, Gordon-Walker, Timothy T., Williams, Mike J., Dunbar, Donald R., Manning, Jonathan R., van Rooijen, Nico, Fallowfield, Jonathan A., Forbes, Stuart J., and Iredale, John P.

Published
2012

24. INFLAMMATION: Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis

Author

Duffin, Rodger, OʼConnor, Richard A., Crittenden, Siobhan, Forster, Thorsten, Yu, Cunjing, Zheng, Xiaozhong, Smyth, Danielle, Robb, Calum T., Rossi, Fiona, Skouras, Christos, Tang, Shaohui, Richards, James, Pellicoro, Antonella, Weller, Richard B., Breyer, Richard M., Mole, Damian J., Iredale, John P., Anderton, Stephen M., Narumiya, Shuh, Maizels, Rick M., Ghazal, Peter, Howie, Sarah E., Rossi, Adriano G., and Yao, Chengcan

Published
2016
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31. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease

Author

Boulter, Luke, Govaere, Olivier, Bird, Tom G., Radulescu, Sorina, Ramachandran, Prakash, Pellicoro, Antonella, Ridgway, Rachel A., Seo, Sang Soo, Spee, Bart, Van Rooijen, Nico, Sansom, Owen J., Iredale, John P., Lowell, Sally, Roskams, Tania, and Forbes, Stuart J.

Subjects
Macrophages -- Physiological aspects -- Genetic aspects -- Research, Cell differentiation -- Physiological aspects -- Genetic aspects -- Research, Liver diseases -- Development and progression -- Genetic aspects -- Research, Wnt proteins -- Physiological aspects -- Genetic aspects -- Research, Biological sciences, Health
Abstract

During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of [...]

Published
2012
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32. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver

Author

Lorenzini, Stefania, Bird, Thomas G., Boulter, Luke, Bellamy, Christopher, Samuel, Kay, Aucott, Rebecca, Clayton, Elizabeth, Andreone, Pietro, Bernardi, Mauro, Golding, Mathew, Alison, Malcolm R., Iredale, John P., and Forbes, Stuart J.

Subjects
Liver cells -- Physiological aspects, Liver cells -- Research, Animal models in research -- Analysis, Stem cell research, Health
Published
2010

34. Progress and future challenges in stem cell-derived liver technologies

Author

Dalgetty, Donna M., Medine, Claire N., Iredale, John P., and Hay, David C.

Subjects
Embryonic stem cells -- Health aspects, Embryonic stem cells -- Genetic aspects, Embryonic stem cells -- Research, Liver cells -- Physiological aspects, Liver cells -- Genetic aspects, Liver cells -- Research, Liver diseases -- Care and treatment, Liver diseases -- Research, Regenerative medicine -- Health aspects, Biological sciences
Abstract

The emergence of regenerative medicine has led to significant advances in the identification and understanding of human stem cells and adult progenitor cells. Both cell populations exhibit plasticity and theoretically offer a potential source of somatic cells in large numbers. Such a resource has an important role to play in the understanding of human development, in modeling human disease and drug toxicity, and in the generation of somatic cells in large numbers for cell-based therapies. Presently, liver transplantation is the only effective treatment for end-stage liver disease. Although this procedure can be carried out with high levels of success, the routine transplant of livers is severely limited by organ donor availability. As a result, attention has focused on the ability to restore liver mass and function by alternative approaches ranging from the bioartificial device to transplantation of human hepatocytes. In this review we will focus on the generation of human hepatic endoderm from different stem/progenitor cell populations with a view to its utility in regenerative medicine. embryonic stem cell; function; hepatocyte; induced pluripotent stem cell

Published
2009

35. Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial

Author

Snowdon, Victoria K., Lachlan, Neil J., Hoy, Anna M., Hadoke, Patrick W. F., Semple, Scott I., Patel, Dilip, Mungall, Will, Kendall, Timothy J., Thomson, Adrian, Lennen, Ross J., Jansen, Maurits A., Moran, Carmel M., Pellicoro, Antonella, Ramachandran, Prakash, Shaw, Isaac, Aucott, Rebecca L., Severin, Thomas, Saini, Rajnish, Pak, Judy, Yates, Denise, Dongre, Neelesh, Duffield, Jeremy S., Webb, David J., Iredale, John P., Hayes, Peter C., and Fallowfield, Jonathan A.

Subjects
Kidney failure -- Risk factors -- Drug therapy -- Research, Renal agents -- Dosage and administration -- Complications and side effects, Liver cirrhosis -- Complications and side effects -- Drug therapy -- Research, Biological sciences
Abstract

Background Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. Methods and findings To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 [mu]g/kg/d and then 60 min at 30 [mu]g/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population. Conclusions Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. Trial registration ClinicalTrials.gov NCT01640964, Author(s): Victoria K. Snowdon 1, Neil J. Lachlan 1, Anna M. Hoy 1, Patrick W. F. Hadoke 2, Scott I. Semple 2,3, Dilip Patel 4, Will Mungall 5, Timothy J. [...]

Published
2017
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38. Prostaglandin E 2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells

Author

Crittenden, Siobhan, primary, Goepp, Marie, additional, Pollock, Jolinda, additional, Robb, Calum T., additional, Smyth, Danielle J., additional, Zhou, You, additional, Andrews, Robert, additional, Tyrrell, Victoria, additional, Gkikas, Konstantinos, additional, Adima, Alexander, additional, O’Connor, Richard A., additional, Davies, Luke, additional, Li, Xue-Feng, additional, Yao, Hatti X., additional, Ho, Gwo-Tzer, additional, Zheng, Xiaozhong, additional, Mair, Amil, additional, Vermeren, Sonja, additional, Qian, Bin-Zhi, additional, Mole, Damian J., additional, Gerasimidis, Konstantinos, additional, Schwarze, Jürgen K. J., additional, Breyer, Richard M., additional, Arends, Mark J., additional, O’Donnell, Valerie B., additional, Iredale, John P., additional, Anderton, Stephen M., additional, Narumiya, Shuh, additional, Maizels, Rick M., additional, Rossi, Adriano G., additional, Howie, Sarah E., additional, and Yao, Chengcan, additional

Published
2021
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41. Distinct Susceptibility to Steatohepatitis and Fibrosis in Dietary Models of Non-Alcoholic Fatty Liver Disease in Mice Associates with Alterations in Intra-Hepatic Glucocorticoid Metabolism

Author

Macfarlane, David P, primary, Nyirenda, Moffat J, additional, Zou, Xiantong, additional, Aucott, Rebecca L, additional, Raubenheimer, Peter J, additional, Michailidou, Zoi, additional, Andrew, Ruth, additional, Iredale, John P, additional, and Walker, Brian R, additional

Published
2011
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