Publications
415 results found
Mohamed NA, Davies R, Lickiss PD, et al., 2016, In Vivo Assessment of Metal Organic Framework (MOFs) for the Future use as Delivery Agents for Drugs to Treat PAH
Pulmonary arterial hypertension (PAH) is a progressive, debilitating and fatal condition with no cure. However small molecule drugs, including sildenafil, selexipag and bosentan, have been developed and are used to treat PAH but do not offer a cure and life expectancy, even on medication, is only between 2-5 years after diagnosis. All PAH drugs are ubiquitous dilators and their therapeutic dose is severely limited by their systemic side-effects [1]. We are working on the hypothesis that current PAH-drugs could be used more effectively at higher local (to the lung) concentrations if delivered selectively using a nanomedicine approach. We suggest that if toxicological limitations of nanomedicines can be overcome their use in PAH to delivery current drugs to the lung could turn this fatal disease to a chronic drug-managedcondition. One nanoparticle that we are interested in is from the Materials of Institute Lavoisier (MIL), the so called MIL-89. MIL-89 is an iron based metal organic framework (MOF). MIL-89 is a good candidate for delivery of drugs because (i) it can be tailored to accommodate different drugs including those with the molecular weights of current PAH-medications (MW; 300-500) [2], (ii) it is biocompatible and biodegradable [3]; (iii) it has a large internal surface area and high drug loading capacity; (iv) it is thermally and mechanically stable; and (v) it promises a long drug release-period with the ability to incorporate different functional groups [2, 4-5]. We have previously shown that MIL-89 at concentrations up to 10µg/ml is non-toxic to human lung cells including those from patients with PAH. In the current study we have investigated the effects of MIL-89 in rats in vivo for markers of toxicity. MIL-89 at 50mg/kg was administered (i.p.) for two weeks at days 0, 1, 3, 7, 10 and 14. At each time point rats were weighed, killed, plasma and tissues collected. MIL-89 had no effect on body weight, lung oedema or on plasma markers of organ failur
Chan MV, Knowles RB, Lundberg MH, et al., 2015, P2Y12 receptor blockade synergises strongly with nitric oxide and prostacyclin to inhibit platelet activation., British Journal of Clinical Pharmacology, Vol: 81, Pages: 621-633, ISSN: 1365-2125
AIMS: In vivo platelet function is a product of intrinsic platelet reactivity, modifiable by dual antiplatelet therapy (DAPT), and the extrinsic inhibitory endothelial mediators, nitric oxide (NO) and prostacyclin (PGI2 ), that are powerfully potentiated by P2Y12 receptor blockade. This implies that for individual patients endothelial mediator production is an important determinant of DAPT effectiveness. Here, we have investigated this idea using platelets taken from healthy volunteers treated with anti-platelet drugs. METHODS: Three groups of male volunteers (n = 8) received either prasugrel (10 mg), aspirin (75 mg) or DAPT (prasugrel + aspirin) once daily for 7 days. Platelet reactivity in the presence of DEA/NONOate and PGI2 was studied before and following treatment. RESULTS: Ex vivo, PGI2 and/or DEA/NONOate had little inhibitory effect on TRAP-6-induced platelet reactivity in control conditions. However, in the presence of DAPT, combination of DEA/NONOate + PGI2 reduced platelet aggregation (74 ± 3% to 19 ± 6%, p < 0.05). In vitro studies showed even partial (25%) P2Y12 receptor blockade produced a significant (67 ± 2% to 39 ± 10%, p < 0.05) inhibition when DEA/NONOate + PGI2 was present. CONCLUSIONS: We demonstrate that PGI2 and NO synergise with P2Y12 receptor antagonists to produce powerful platelet inhibition. Furthermore, even with submaximal P2Y12 blockade the presence of PGI2 and NO greatly enhances platelet inhibition. Our findings highlight the importance of endothelial mediator in vivo modulation of P2Y12 inhibition and introduces the concept of refining ex vivo platelet function testing by incorporating an assessment of endothelial function to better predict thrombotic outcomes and adjust therapy to prevent adverse outcomes in individual patients.
Kirkby NS, Reed DM, Edin ML, et al., 2015, Inherited human group IVA cytosolic phospholipase A(2) deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation, The FASEB Journal, Vol: 29, Pages: 4568-4578, ISSN: 0892-6638
Eicosanoids are important vascular regulators,but the phospholipase A2 (PLA2) isoforms supportingtheir production within the cardiovascular systemare not fully understood. To address this, we have studiedplatelets, endothelial cells, and leukocytes from 2 siblingswith a homozygous loss-of-function mutation in group IVAcytosolic phospholipase A2 (cPLA2a). Chromatography/mass spectrometry was used to determine levels of a broadrange of eicosanoids produced by isolated vascular cells,and in plasma and urine. Eicosanoid release data werepaired with studies of cellular function. Absence ofcPLA2a almost abolished eicosanoid synthesis in platelets(e.g., thromboxane A2, control 20.5 6 1.4 ng/ml vs. patient0.1 ng/ml) and leukocytes [e.g., prostaglandin E2 (PGE2),control 21.9 6 7.4 ng/ml vs. patient 1.9 ng/ml], and thiswas associated with impaired platelet activation and enhancedinflammatory responses. cPLA2a-deficient endothelialcells showed reduced, but not absent, formation ofprostaglandin I2 (prostacyclin; control 956 6 422 pg/ml vs.patient 196 pg/ml) and were primed for inflammation.In the urine, prostaglandin metabolites were selectivelyinfluenced by cPLA2a deficiency. For example, prostacyclinmetabolites were strongly reduced (18.4% of control)in patients lacking cPLA2a, whereas PGE2 metabolites(77.8% of control) were similar to healthy volunteer levels.These studies constitute a definitive account, demonstratingthe fundamental role of cPLA2a to eicosanoid formationand cellular responses within the human circulation.
Ahmetaj-Shala B, Kirkby NS, Knowles R, et al., 2015, Reply to Letter Regarding Article, “Evidence That Links Loss of Cyclooxygenase-2 With Increased Asymmetric Dimethylarginine: Novel Explanation of Cardiovascular Side Effects Associated With Anti-Inflammatory Drugs”, Circulation, Vol: 132, Pages: E213-E214, ISSN: 0009-7322
Marei I, Carubelli I, Reed DM, et al., 2015, The Interaction between Human Blood Endothelial Cells and Polycaprolactone Scaffolds, 4th TERMIS World Congress, Publisher: MARY ANN LIEBERT, INC, Pages: S151-S151, ISSN: 1937-3341
Francis C, Freidin MB, Gashaw H, et al., 2015, Shear stress pattern regulates aortic endothelial cell transcriptome: global gene expression profiles and implications for aortic disease, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 35-35, ISSN: 0195-668X
Reed DM, Paschalaki KE, Starke RD, et al., 2015, An autologous endothelial cell: peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics, The FASEB Journal, Vol: 29, Pages: 2595-2602, ISSN: 0892-6638
There is an urgent unmet need for human tissue bioassays to predict cytokine storm responses to biologics. Current bioassays that detect cytokine storm responses in vitro rely on endothelial cells, usually from umbilical veins or cell lines, cocultured with freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy adult volunteers. These assays therefore comprise cells from 2 separate donors and carry the disadvantage of mismatched tissues and lack the advantage of personalized medicine. Current assays also do not fully delineate mild (such as Campath) and severe (such as TGN1412) cytokine storm‐inducing drugs. Here, we report a novel bioassay where endothelial cells grown from stem cells in the peripheral blood (blood outgrowth endothelial cells) and PBMCs from the same donor can be used to create an autologous coculture bioassay that responds by releasing a plethora of cytokines to authentic TGN1412 but only modestly to Campath and not to control antibodies such as Herceptin, Avastin, and Arzerra. This assay performed better than the traditional mixed donor assay in terms of cytokine release to TGN1412 and, thus, we suggest provides significant advancement and a definitive system by which biologics can be tested and paves the way for personalized medicine.—Reed, D. M., Paschalaki, K. E., Starke, R. D., Mohamed, N. A., Sharp, G., Fox, B., Eastwood, D., Bristow, A., Ball, C., Vessillier, S., Hansel, T. T., Thorpe, S. J., Randi, A. M., Stebbings, R., Mitchell, J. A. An autologous endothelial cell:peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics. FASEB J. 29, 2595‐2602 (2015). www.fasebj.org
Chakrabarti AM, Mitchell JA, Wort SJ, 2015, Progress in the understanding and management of pulmonary arterial hypertension., Global Cardiology Science & Practice, Vol: 2015, ISSN: 2305-7823
Schoenfelder S, Furlan-Magaril M, Mifsud B, et al., 2015, The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements, Genome Research, Vol: 25, Pages: 582-597, ISSN: 1549-5469
The mammalian genome harbors up to one million regulatory elements often located at great distances from their target genes. Long-range elements control genes through physical contact with promoters and can be recognized by the presence of specific histone modifications and transcription factor binding. Linking regulatory elements to specific promoters genome-wide is currently impeded by the limited resolution of high-throughput chromatin interaction assays. Here we apply a sequence capture approach to enrich Hi-C libraries for >22,000 annotated mouse promoters to identify statistically significant, long-range interactions at restriction fragment resolution, assigning long-range interacting elements to their target genes genome-wide in embryonic stem cells and fetal liver cells. The distal sites contacting active genes are enriched in active histone modifications and transcription factor occupancy, whereas inactive genes contact distal sites with repressive histone marks, demonstrating the regulatory potential of the distal elements identified. Furthermore, we find that coregulated genes cluster nonrandomly in spatial interaction networks correlated with their biological function and expression level. Interestingly, we find the strongest gene clustering in ES cells between transcription factor genes that control key developmental processes in embryogenesis. The results provide the first genome-wide catalog linking gene promoters to their long-range interacting elements and highlight the complex spatial regulatory circuitry controlling mammalian gene expression.
Mitchell JA, Ahmetaj-Shala B, Kirkby NS, et al., 2015, Role of prostacyclin in pulmonary hypertension., Global Cardiology Science and Practice, Vol: 2014, Pages: 382-393, ISSN: 2305-7823
Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it's discovery in the 1970s concerted efforts have been made to make the best therapeutic utility of prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of prostacyclin but that target the receptors that prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to prostacyclin and its use in pulmonary arterial hypertension.
Ahmetaj-Shala B, Kirkby NS, Knowles R, et al., 2015, Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine novel explanation of cardiovascular side effects associated with anti-inflammatory drugs, Circulation, Vol: 131, Pages: 633-U113, ISSN: 0009-7322
Background—Cardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern. Cyclooxygenase-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygenase-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified.Methods and Results—Transcriptome analysis of wild-type and cyclooxygenase-2−/− mouse tissues revealed 1 gene altered in the heart and aorta, but >1000 genes altered in the renal medulla, including those regulating the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and monomethyl-l-arginine. Cyclo-oxygenase-2−/− mice had increased plasma levels of ADMA and monomethyl-l-arginine and reduced endothelial nitric oxide responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors. Wild-type mice or human volunteers taking cyclooxygenase-2 inhibitors also showed increased plasma ADMA. Endothelial nitric oxide is cardio-protective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA is associated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction with nonsteroidal anti-inflammatory drug usage.Conclusions—We identify the endogenous endothelial nitric oxide synthase inhibitor ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction.
Ahmetaj-Shala B, Kirkby NS, Knowles R, et al., 2015, Evidence That Links Loss of Cyclooxygenase-2 With Increased Asymmetric Dimethylarginine, Publisher: Ovid Technologies (Wolters Kluwer Health), Pages: 633-642, ISSN: 0009-7322
<jats:sec> <jats:title>Background—</jats:title> <jats:p>Cardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern. Cyclooxygenase-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygenase-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> Transcriptome analysis of wild-type and cyclooxygenase-2 <jats:sup>−/−</jats:sup> mouse tissues revealed 1 gene altered in the heart and aorta, but >1000 genes altered in the renal medulla, including those regulating the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and monomethyl- <jats:sc>l</jats:sc> -arginine. Cyclo-oxygenase-2 <jats:sup>−/−</jats:sup> mice had increased plasma levels of ADMA and monomethyl- <jats:sc>l</jats:sc> -arginine and reduced endothelial nitric oxide responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors. Wild-type mice or human volunteers taking cyclooxygenase-2 inhibitors also showed increased plasma ADMA. Endothelial nitric oxide is cardio-protective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA is associated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction with nonsteroidal anti-inflammatory drug usage. </jats:p> </jats:sec> <jats:sec&g
Reed DM, George PM, Mitchell JA, 2015, Letter by Reed et al Regarding Article, "Proteomic Analysis Implicates Translationally Controlled Tumor Protein as a Novel Mediator of Occlusive Vascular Remodeling in Pulmonary Arterial Hypertension", CIRCULATION, Vol: 131, Pages: E346-E346, ISSN: 0009-7322
Ross CL, Galloway-Phillipps N, Armstrong PC, et al., 2015, Protocol for a human in vivo model of acute cigarette smoke inhalation challenge in smokers with COPD: monitoring the nasal and systemic immune response using a network biology approach, BMJ OPEN, Vol: 5, ISSN: 2044-6055
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- Citations: 3
Reed DM, Foldes G, Kirkby NS, et al., 2014, Morphology and vasoactive hormone profiles from endothelial cells derived from stem cells of different sources, Biochemical and Biophysical Research Communications, Vol: 455, Pages: 172-177, ISSN: 1090-2104
Kirkby NS, Lundberg MH, Wright WR, et al., 2014, COX-2 protects against atherosclerosis independently of local vascular prostacyclin: Identification of COX-2 associated pathways implicate Rgl1 and lymphocyte networks, PLoS ONE, Vol: 9, ISSN: 1932-6203
George PM, Wort SJ, Mitchell JA, 2014, Proteome-wide Analysis and CXCL4 in Systemic Sclerosis, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 370, Pages: 1561-1562, ISSN: 0028-4793
George PM, Wort SJ, Mitchell JA, 2014, Proteome-wide Analysis and CXCL4 in Systemic Sclerosis, New England Journal of Medicine, Vol: 370, Pages: 1561-1562
George PM, Wort SJ, Mitchell JA, 2014, Use of interferon beta for acute respiratory distress syndrome: proceed with caution., The Lancet Respiratory Medicine, Vol: 2
Reed DM, Foldes G, Gatheral T, et al., 2014, Pathogen Sensing Pathways in Human Embryonic Stem Cell Derived-Endothelial Cells: Role of NOD1 Receptors, PLOS One, Vol: 9, ISSN: 1932-6203
Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis. Here, we have compared TLR4 and NOD1 responses in hESC-EC with those of endothelial cells derived from other stem cells and with human umbilical vein endothelial cells (HUVEC). HUVEC, endothelial cells derived from blood progenitors (blood outgrowth endothelial cells; BOEC), and from induced pluripotent stem cells all displayed both a TLR4 and NOD1 response. However, hESC-EC had no TLR4 function, but did have functional NOD1 receptors. In vivo conditioning in nude rats did not confer TLR4 expression in hESC-EC. Despite having no TLR4 function, hESC-EC sensed Gram-negative bacteria, a response that was found to be mediated by NOD1 and the associated RIP2 signalling pathways. Thus, hESC-EC are TLR4 deficient but respond to bacteria via NOD1. This data suggests that hESC-EC may be protected from unwanted TLR4-mediated vascular inflammation, thus offering a potential therapeutic advantage.
George PM, Oliver E, Dorfmuller P, et al., 2014, Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension, CIRCULATION RESEARCH, Vol: 114, Pages: 677-688, ISSN: 0009-7330
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- Citations: 98
Wright WR, Paschalaki KE, Gashaw HH, et al., 2013, Characterisation of the phospholipase A2 isoforms supporting prostacyclin production synthesis by endothelial cells, Pharmacology 2013
Brooke MA, Longhurst HJ, Plagnol V, et al., 2013, Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-alpha, GUT, Vol: 63, Pages: 96-104, ISSN: 0017-5749
Kojonazarov B, Luitel H, Sydykov A, et al., 2013, The peroxisome proliferator-activated receptor β/δ agonist GW0742 has direct protective effects on right heart hypertrophy, PULMONARY CIRCULATION, Vol: 3, Pages: 926-935, ISSN: 2045-8932
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- Citations: 18
Wright WR, Kirkby NS, Galloway-Phillipps NA, et al., 2013, Cyclooxygenase and cytokine regulation in lung fibroblasts activated with viral versus bacterial pathogen associated molecular patterns, PROSTAGLANDINS & OTHER LIPID MEDIATORS, Vol: 107, Pages: 4-12, ISSN: 1098-8823
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- Citations: 6
George PM, Oliver E, Schreiber BE, et al., 2013, EVIDENCE THAT TYPE I INTERFERON DRIVES PULMONARY ARTERIAL HYPERTENSION, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A73-A74, ISSN: 0040-6376
Price LC, Paul-Clark M, Meng C, et al., 2013, PERIPHERAL BLOOD MONONUCLEAR CELLS FROM PATIENTS WITH IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION ARE HYPORESPONSIVE TO INFLAMMATORY STIMULI, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A147-A148, ISSN: 0040-6376
Kirkhy NS, Wright WR, Warner TD, et al., 2013, COX-2 and Cardiovascular Risk; Identification of New COX-2 Targets and Pathways Outside the Vessel Wall, Scientific Sessions and Resuscitation Science Symposium of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Ahmetaj-Shala B, Kirkby NS, Al-yamani M, et al., 2013, Evidence That Links Cyclo-oxygenase-2 Inhibition With Increased Asymmetric Dimethylarginine: Novel Explanation of Cardiovascular Side Effects Associated With Anti-inflammatory Drugs, Scientific Sessions and Resuscitation Science Symposium of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Kirkby NS, Chan MV, Lundberg MH, et al., 2013, Aspirin-triggered 15-epi-lipoxin A<sub>4</sub> predicts cyclooxygenase-2 in the lungs of LPS-treated mice hut not in the circulation: implications for a clinical test, FASEB JOURNAL, Vol: 27, Pages: 3938-3946, ISSN: 0892-6638
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- Citations: 15
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