D J Fitzgerald

University College Dublin, Dublin, L, Ireland

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Publications (221)1525.01 Total impact

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    ABSTRACT: Conjugated linoleic acid (CLA) has the unique property of inducing regression of pre-established murine atherosclerosis. Understanding the mechanism(s) involved may help identify endogenous pathways that reverse human atherosclerosis. Here, we provide evidence that CLA inhibits foam cell formation via regulation of the nuclear receptor coactivator, peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, and that macrophage PGC-1α plays a role in atheroprotection in vivo. PGC-1α was identified as a hub gene within a cluster in the aorta of the apoE(-/-) mouse in the CLA-induced regression model. PGC-1α was localized to macrophage/foam cells in the murine aorta where its expression was increased during CLA-induced regression. PGC-1α expression was also detected in macrophages in human atherosclerosis and was inversely linked to disease progression in patients with the disease. Deletion of PGC-1α in bone marrow derived macrophages promoted, whilst over expression of the gene inhibited foam cell formation. Importantly, macrophage specific deletion of PGC-1α accelerated atherosclerosis in the LDLR(-/-) mouse in vivo. These novel data support a functional role for PGC-1α in atheroprotection.
    EMBO Molecular Medicine 08/2013; · 7.80 Impact Factor
  • Simone Marcone, Desmond J Fitzgerald
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    ABSTRACT: 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) is an endogenous anti-inflammatory lipid derived from PGD2 . One potential mechanism for its activity is the covalent modification of cellular proteins, via a reactive α,β-unsaturated carbonyl group in its cyclopentenone ring, which in turn alters protein function. In order to identify the candidate target proteins covalently modified by 15d-PGJ2 in human aortic endothelial cell (EC), EC were treated with biotinylated-15d-PGJ2, the modified proteins extracted by Neutravidin affinity-purification and the proteins identified by LTQ Orbitrap mass spectrometer. Classification of the 358 identified proteins was performed using PANTHER classification system (www.pantherdb.org), showing that the proteins mapped to metabolic process, cellular process and transport activity. This protein data set highlights the potential for 15d-PGJ2 to covalently modify cellular proteins and provides a source of data that will aid further studies on the mechanism of action of this endogenous regulator of inflammation. This article is protected by copyright. All rights reserved.
    Proteomics 04/2013; · 4.43 Impact Factor
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    ABSTRACT: Wnt signaling is involved in numerous aspects of vertebrate development and homeostasis, including the formation and function of blood cells. Here, we show that canonical and non-canonical Wnt signaling pathways are present and functional in megakaryocytes (MKs), with several Wnt effectors displaying MK-restricted expression. Using the CHRF288-11 cell line as a model for human MKs, the canonical Wnt3a signal was found to induce a time- and dose-dependent increase in β-catenin expression. β-catenin accumulation was inhibited by the canonical antagonist dickkopf-1 (DKK1) and by the non-canonical agonist Wnt5a. Whole genome expression analysis demonstrated that Wnt3a and Wnt5a regulated distinct patterns of gene expression in MKs, and revealed a further interplay between canonical and non-canonical Wnt pathways. Fetal liver cells derived from low-density-lipoprotein receptor-related protein 6-deficient mice (LRP6(-/-)), generated dramatically reduced numbers of MKs in culture of lower ploidy (2N and 4N) than wildtype controls, implicating LRP6-dependent Wnt signaling in MK proliferation and maturation. Finally, in wildtype mature murine fetal liver-derived MKs, Wnt3a potently induced proplatelet formation, an effect that could be completely abrogated by DKK1. These data identify novel extrinsic regulators of proplatelet formation, and reveal a profound role for Wnt signaling in platelet production.
    Blood 11/2012; · 9.78 Impact Factor
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    ABSTRACT: Recruitment of monocytes to the damaged endothelium characterizes the early stages of atherosclerosis. Conjugated linoleic acids (CLA) are a group of naturally occurring fatty acids which inhibit the progression and induce regression of pre-established atherosclerosis. We have previously shown that CLA inhibits human peripheral blood monocyte (HPBMC) migration. Here we demonstrate that CLA suppresses adhesion of monocytes to endothelial cells, via inhibition of β2 integrins. We further show that CLA suppresses the CXCR4 signalling pathway thus inhibiting crawling of monocytes towards CXCL12 chemokine. HPBMCs were treated with 10uM of CLA isomers (c9,t11-CLA and t10,c12-CLA), a CLA blend (80:20, c9t,11:t10,c12), control lipids and 5uM of PPAR{gamma} agonist (troglitazone) prior to adhesion to HAECs. c9,t11-CLA and CLA blend treatment inhibited monocyte adhesion to HAECs (63±3%, p<0.01 and 68±3%, p<0.01, respectively). Furthermore, c9,t11-CLA and CLA blend inhibited CD18, the β chain of β2 integrin, mRNA (48±14%, p<0.05 and 35±3%, p<0.001) and protein expression (44±13%, p<0.05, and 35±3%, p<0.001) via a PPAR{gamma}[[Unable to Display Character: ]]dependent mechanism. Flow cytometry analysis showed that c9,t11-CLA and CLA blend decreased external surface expression of both β chain (10±4%, p<0.05 and 20±5%, p<0.01), and α subunits (CD11a, 13±6%, p<0.05 and 30±5%, p<0.01; CD11b, 8±3%, p<0.05 and 27±7%, p<0.01), suggesting that CLA’s effect on CD18 transcription results in dysfunctional αβ complex formation, altering expression of LFA-1 and Mac-1 integrins. Furthermore, c9,t11-CLA and CLA blend almost completely abolished (by 82% and 89%, p<0.001) adhesion of monocytes to ICAM-1. Immunocytochemistry of adherent cells further confirmed the inhibition of cell spreading. Importantly, CLA suppresses monocyte response to chemoattraction, preventing crawling of cells through a reduction, of CXCR4 expression (c9,t11-CLA, 47±10%, p<0.05; CLA blend, 33±5%, p<0.01). Our findings suggest that CLA inhibits monocyte recruitment by suppressing their sensitivity to chemokines and by inhibiting their ability to firmly attach to ICAM-1.
    American Heart Association - Scientific Sessions 2012; 11/2012
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    ABSTRACT: Conjugated linoleic acid (CLA) induces regression of preestablished atherosclerosis in the ApoE(-/-) mouse. Understanding the mechanisms involved may help in identifying novel pathways associated with the regression of human disease. Animals were administered a 1% cholesterol diet for 12 wk, with 1% CLA supplementation from wk 8 to 12. ApoE(-/-) mice fed only the 1% cholesterol diet for 12 wk were employed as controls. Transcriptomic analysis of mouse aorta showed that many of the components of the IL-10 signaling pathway were modified during CLA-induced regression. Real-time PCR and Western blot analysis showed increased IL-10 receptor expression, phosphorylation of STAT3, and downstream target gene expression in the aorta, alongside an increase in serum IL-10 (79.8±22.4 vs. 41.9±5.5 pg/ml, n=10; P<0.01). CLA -supplementation also increased IL-10 production in bone marrow-derived macrophages (143.6±28.6 vs. 94±5.6 pg/ml, n=5; P<0.05). To explore the mechanisms for altered IL-10 production, we examined the profile of monocyte/macrophage phenotype in the vessel wall, bone marrow, and spleen. CLA increased macrophage polarization toward an anti-inflammatory M2 phenotype in vivo, increasing the population of Ly6C(lo) monocytes (29 vs. 77±14, n=5, P < 0.05) in the aorta. CLA had similar effects on monocytes/macrophages differentiated from marrow-derived progenitor cells and on splenocytes. The induction of IL-10 on CLA supplementation in this model may reflect a systemic alteration toward an anti-inflammatory phenotype, which, in turn promotes increased vascular infiltration by Ly6C(lo) monocytes. These cells may contribute to CLA-induced disease regression.-McCarthy, C., Duffy, M. M., Mooney, D., James, W. G., Griffin, M. D., Fitzgerald, D. J., Belton, O. IL-10 mediates the immunoregulatory response in conjugated linoleic acid-induced regression of atherosclerosis.
    The FASEB Journal 10/2012; · 5.70 Impact Factor
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    ABSTRACT: Here we provide evidence that WNT-3a modulates platelet function by regulating the activity of four key GTPase proteins: Rap1, Cdc42, Rac1 and RhoA. We observe WNT-3a to differentially regulate small GTPase activity in platelets, promoting the GDP-bound form of Rap1b to inhibit integrin-α(IIb)β(3) adhesion, while concomitantly increasing Cdc42 and Rac1-GTP levels thereby disrupting normal platelet spreading. We demonstrate that Daam-1 interacts with Dishevelled upon platelet activation, which correlates with increased RhoA-GTP levels. Upon pre-treatment with WNT-3a, this complex disassociates, concurrent with a reduction in RhoA-GTP. Together these data implicate WNT-3a as a novel upstream regulator of small GTPase activity in platelets.
    FEBS letters 06/2012; 586(16):2267-72. · 3.54 Impact Factor
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    ABSTRACT: Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, cross-linked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1 [leucine-rich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response.
    Blood 11/2010; 116(22):4646-56. · 9.78 Impact Factor
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    ABSTRACT: We have previously shown that CLA induces regression of pre-established atherosclerotic lesions in apoE(-/-) mice. CLA is a known ligand of peroxisome proliferator activated receptors (PPARs) and it is postulated that CLA mediates its atheroprotective effects through activation of PPARs. Earlier work in our group identified the monocyte/macrophage cell as the primary cellular target of CLA. In this study we identified novel genes regulated by CLA during the regression of atherosclerosis and characterised a role for one of these, SorLA. SorLA is a member of the vacuolar protein sorting 10 protein (Vps10p) domain receptor family, which has structural homology with the LDLR family. Expression of SorLA was identified with its Vps10p family member Sort1 by transcriptomic analysis of murine aorta following CLA-induced regression of atherosclerosis. Decreased expression of both receptors was confirmed by real-time PCR in the aorta of CLA-supplemented mice. SorLA protein expression was predominantly localised to monocyte/macrophage cells in the vasculature by immunohistochemistry. CLA and the PPAR-γ agonists, troglitazone, and 15-deoxy-prostaglandin (PG) J(2), decreased protein and RNA expression of SorLA in THP-1 monocytes; while pre-treatment with a PPAR-γ antagonist established a PPAR-γ dependent role for CLA regulation of SorLA. CLA inhibits monocyte migration. Consistent with a role for SorLA in mediating this response, overexpression of SorLA increased migration of THP-1 monocytes to monocyte chemoattractant protein-1 with a coincident increase in UPAR expression. CLA may mediate its atheroprotective effects in part through reduced expression of SorLA and a resulting inhibition of monocyte migration in vitro.
    Atherosclerosis 10/2010; 213(2):400-7. · 3.71 Impact Factor
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    ABSTRACT: Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G-protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41-amino-acid deletion) of the human G-protein beta3 (Gbeta3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity. To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. GNB3 genotype distribution was determined in DNA samples from patients in the orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction (OPUS-TIMI) 16 genetic sub-study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re-hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non-T carriers treated with orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55-1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58-4.35, P < 0.001). Interaction between T allele carriership and treatment was not significant for the primary endpoint (P = 0.18) or MI (P = 0.69). The GNB3 T allele significantly increased bleeding in patients treated with the platelet antagonist orbofiban. Our findings suggest that risk of bleeding associated with an antiplatelet agent is heritable and may be dissociated from risk of thrombosis.
    Journal of Thrombosis and Haemostasis 05/2010; 8(5):934-41. · 6.08 Impact Factor
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    ABSTRACT: The signaling molecule 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) has been described as the "anti-inflammatory prostaglandin." Here we show that substrates of the nuclear export receptor CRM1 accumulate in the nucleus in the presence of 15d-PGJ(2), identifying this prostaglandin as a regulator of CRM1-dependent nuclear protein export that can be produced endogenously. Like leptomycin B (LMB), an established fungal CRM1-inhibitor, 15d-PGJ(2) reacts with a conserved cysteine residue in the CRM1 sequence. This covalent modification prevents the formation of nuclear export complexes. Cells that are transfected with mutant CRM1 (C528S) are resistant to the inhibitory effects of LMB and 15d-PGJ(2), demonstrating that the same single amino acid is targeted by the two compounds. Inhibition of the CRM1 pathway by endogenously produced prostaglandin and/or exogenously applied 15d-PGJ(2) may contribute to its anti-inflammatory, anti-proliferative, and anti-viral effects.
    Journal of Biological Chemistry 05/2010; 285(29):22202-10. · 4.65 Impact Factor
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    ABSTRACT: Proteomic approaches have proven powerful at identifying large numbers of proteins, but there are fewer reports of functional characterization of proteins in biological tissues. Here, we describe an experimental approach that fractionates proteins released from human platelets, linking bioassay activity to identity. We used consecutive orthogonal separation platforms to ensure sensitive detection: (a) ion-exchange of intact proteins, (b) SDS-PAGE separation of ion-exchange fractions and (c) HPLC separation of tryptic digests coupled to electrospray tandem mass spectrometry. Migration of THP-1 monocytes in response to complete or fractionated platelet releasate was assessed and located to just one of the forty-nine ion-exchange fractions. Over 300 proteins were identified in the releasate, with a wide range of annotated biophysical and biochemical properties, in particular platelet activation, adhesion, and wound healing. The presence of PEDF and involucrin, two proteins not previously reported in platelet releasate, was confirmed by western blotting. Proteins identified within the fraction with monocyte promigratory activity and not in other inactive fractions included vimentin, PEDF, and TIMP-1. We conclude that this analytical platform is effective for the characterization of complex bioactive samples.
    BioMed Research International 01/2010; 2010:107859. · 2.88 Impact Factor
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    ABSTRACT: Wnts regulate important intracellular signaling events, and dysregulation of the Wnt pathway has been linked to human disease. Here, we uncover numerous Wnt canonical effectors in human platelets where Wnts, their receptors, and downstream signaling components have not been previously described. We demonstrate that the Wnt3a ligand inhibits platelet adhesion, activation, dense granule secretion, and aggregation. Wnt3a also altered platelet shape change and inhibited the activation of the small GTPase RhoA. In addition, we found the Wnt-beta-catenin signaling pathway to be functional in platelets. Finally, disruption of the Wnt Frizzled 6 receptor in the mouse resulted in a hyperactivatory platelet phenotype and a reduced sensitivity to Wnt3a. Taken together our studies reveal a novel functional role for Wnt signaling in regulating anucleate platelet function and may provide a tractable target for future antiplatelet therapy.
    Proceedings of the National Academy of Sciences 11/2009; 106(47):19836-41. · 9.81 Impact Factor
  • Lorna M Cryan, Desmond J Fitzgerald, Colm O'Brien
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    ABSTRACT: Prostaglandins have many important roles in ocular physiology and are used clinically for the treatment of glaucoma. The aim of this study was to analyse the contribution of each cyclooxygenase isoform to ocular prostaglandin production using isoform-specific knockout mice. Ex vivo PGE(2), 6-keto-PGF(1alpha), and TXB(2) production was measured from whole eyes, corneal tissue, uveoscleral tissue, lens, retina and optic nerve using enzyme-linked immunosorbant assays. Ocular immunohistochemical and histological analysis was also conducted for each genotype. Levels of each of the prostaglandins measured were significantly decreased in the corneal tissue, uveoscleral tissue, lens, retina and optic nerve of COX-1(-/-) mice in comparison with wild-type mice. In contrast, COX-2(-/-) mice had similar levels of ocular prostaglandin production to wild-type mice. These results suggest that COX-1 is the principal isoform responsible for prostaglandin production in the mouse eye. The absence of COX-1 or COX-2 did not appear to effect ocular development in these mice.
    Prostaglandins Leukotrienes and Essential Fatty Acids 09/2009; 81(5-6):401-9. · 2.73 Impact Factor
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    ABSTRACT: Cyclooxygenase-2 (COX-2) is over-expressed in colorectal cancer (CRC), rendering tumour cells resistant to apoptosis. Selective COX-2 inhibition is effective in CRC prevention, although having adverse cardiovascular effects, thus focus has shifted to downstream pathways. Microarray experiments identified genes regulated by COX-2 in HCA7 CRC cells. In vitro and in vivo regulation of DRAK2 (DAP kinase-related apoptosis-inducing kinase 2 or STK17beta, an apoptosis-inducing kinase) by COX-2 was validated by qRT-PCR. Inhibition of COX-2 induced apoptosis and enhanced DRAK2 expression in HCA7 cells (4.4-fold increase at 4 h by qRT-PCR, P=0.001), an effect prevented by co-administration of PGE(2). DRAK2 levels were suppressed in a panel of human colorectal tumours (n=10) compared to normal mucosa, and showed inverse correlation with COX-2 expression (R=-0.68, R2=0.46, P=0.03). Administration of the selective COX-2 inhibitor rofecoxib to patients with CRC (n=5) induced DRAK2 expression in tumours (2.5-fold increase, P=0.01). In vitro silencing of DRAK2 by RNAi enhanced CRC cell survival following COX-2 inhibitor treatment. DRAK2 is a serine-threonine kinase implicated in the regulation of apoptosis and is negatively regulated by COX-2 in vitro and in vivo, suggesting a novel mechanism for the effect of COX-2 on cancer cell survival.
    British Journal of Cancer 09/2009; 101(3):483-91. · 5.08 Impact Factor
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    ABSTRACT: Prostaglandin E2 (PGE2) is the major product of Cyclooxygenase-2 (COX-2) in colorectal cancer (CRC). We aimed to assess PGE2 cell surface receptors (EP 1-4) to examine the mechanisms by which PGE2 regulates tumour progression. Gene expression studies were performed by quantitative RT-PCR. Cell cycle was analysed by flow cytometry with cell proliferation quantified by BrdU incorporation measured by enzyme immunoassay. Immunohistochemistry was employed for expression studies on formalin fixed paraffin embedded tumour tissue. EP4 was the most abundant subtype of PGE2 receptor in HT-29 and HCA7 cells (which show COX-2 dependent PGE2 generation) and was consistently the most abundant transcript in human colorectal tumours (n = 8) by qRT-PCR (ANOVA, p = 0.01). G0/G1 cell cycle arrest was observed in HT-29 cells treated with SC-236 5 microM (selective COX-2 inhibitor) for 24 hours (p = 0.02), an effect abrogated by co-incubation with PGE2 (1 microM). G0/G1 arrest was also seen with a specific EP4 receptor antagonist (EP4A, L-161982) (p = 0.01). Treatment of HT-29 cells with either SC-236 or EP4A caused reduction in intracellular cAMP (ANOVA, p = 0.01). Early induction in p21WAF1/CIP1 expression (by qRT-PCR) was seen with EP4A treatment (mean fold increase 4.4, p = 0.04) while other genes remained unchanged. Similar induction in p21WAF1/CIP1 was also seen with PD153025 (1 microM), an EGFR tyrosine kinase inhibitor, suggesting EGFR transactivation by EP4 as a potential mechanism. Additive inhibition of HCA7 proliferation was observed with the combination of SC-236 and neutralising antibody to amphiregulin (AR), a soluble EGFR ligand. Concordance in COX-2 and AR localisation in human colorectal tumours was noted. COX-2 regulates cell cycle transition via EP4 receptor and altered p21WAF1/CIP1 expression. EGFR pathways appear important. Specific targeting of the EP4 receptor or downstream targets may offer a safer alternative to COX-2 inhibition in the chemoprevention of CRC.
    BMC Cancer 07/2009; 9:207. · 3.33 Impact Factor
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    ABSTRACT: Abstract Background Prostaglandin E<sub>2 </sub>(PGE<sub>2</sub>) is the major product of Cyclooxygenase-2 (COX-2) in colorectal cancer (CRC). We aimed to assess PGE<sub>2 </sub>cell surface receptors (EP 1–4) to examine the mechanisms by which PGE<sub>2 </sub>regulates tumour progression. Methods Gene expression studies were performed by quantitative RT-PCR. Cell cycle was analysed by flow cytometry with cell proliferation quantified by BrdU incorporation measured by enzyme immunoassay. Immunohistochemistry was employed for expression studies on formalin fixed paraffin embedded tumour tissue. Results EP4 was the most abundant subtype of PGE<sub>2 </sub>receptor in HT-29 and HCA7 cells (which show COX-2 dependent PGE<sub>2 </sub>generation) and was consistently the most abundant transcript in human colorectal tumours (n = 8) by qRT-PCR (ANOVA, p = 0.01). G0/G1 cell cycle arrest was observed in HT-29 cells treated with SC-236 5 μM (selective COX-2 inhibitor) for 24 hours (p = 0.02), an effect abrogated by co-incubation with PGE<sub>2 </sub>(1 μM). G0/G1 arrest was also seen with a specific EP4 receptor antagonist (EP4A, L-161982) (p = 0.01). Treatment of HT-29 cells with either SC-236 or EP4A caused reduction in intracellular cAMP (ANOVA, p = 0.01). Early induction in p21<sup>WAF1/CIP1 </sup>expression (by qRT-PCR) was seen with EP4A treatment (mean fold increase 4.4, p = 0.04) while other genes remained unchanged. Similar induction in p21<sup>WAF1/CIP1 </sup>was also seen with PD153025 (1 μM), an EGFR tyrosine kinase inhibitor, suggesting EGFR transactivation by EP4 as a potential mechanism. Additive inhibition of HCA7 proliferation was observed with the combination of SC-236 and neutralising antibody to amphiregulin (AR), a soluble EGFR ligand. Concordance in COX-2 and AR localisation in human colorectal tumours was noted. Conclusion COX-2 regulates cell cycle transition via EP4 receptor and altered p21<sup>WAF1/CIP1 </sup>expression. EGFR pathways appear important. Specific targeting of the EP4 receptor or downstream targets may offer a safer alternative to COX-2 inhibition in the chemoprevention of CRC.
    BMC Cancer. 01/2009;
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    ABSTRACT: Nonsteroidal anti-inflammatory drugs with a selective cyclooxygenase-2 (COX-2) inhibitory profile are effective analgesics in the postoperative period. This implies that surgery induces COX-2 biosynthesis. We examined whether peripheral surgical trauma can induce COX-2 expression in the rat cervical spinal cord. Sprague-Dawley rats were divided into 2 groups. The control group underwent general anesthesia but had no surgery. The surgical group underwent general anesthesia and surgical exposure of neck structures. After 14 days, the animals were euthanized, and a section of cervical spinal cord was taken to identify COX-1 and COX-2 expression by immunohistochemical analysis. Two independent blinded observers analyzed the slides. Analysis of COX-1 protein expression revealed homogenous staining in glial cells in all regions of the cervical spinal cord examined. There was no difference in expression between the control and surgical groups. However, whereas the control group demonstrated minimal COX-2 expression, the surgical group showed extensive neuronal and glial cell cytoplasmic COX-2 expression. This study demonstrates that surgery induces COX-2 expression in the rat cervical spinal cord. This could provide a scientific rationale for the use of selective COX-2 inhibitors as analgesics in the postoperative period.
    Regional anesthesia and pain medicine 01/2009; 34(6):549-52. · 4.16 Impact Factor
  • Ref. No: WO2009127398, Year: 01/2009
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    ABSTRACT: Basic calcium phosphate (BCP) crystals have been implicated in the pathogenesis of osteoarthritis (OA), in part because of their ability to upregulate cyclooxygenase and prostaglandin E(2) (PGE(2)) production. The aim of this work was to investigate the expression of terminal PGE(2) synthases and PGE(2) receptors (EP) in BCP crystal-stimulated fibroblasts. Cultured fibroblasts were stimulated with BCP crystals in vitro. mRNA expression was measured by real-time polymerase chain reaction, and protein production by western blotting. Basal expression of microsomal prostaglandin E(2) synthase 1 (mPGES1) in osteoarthritic synovial fibroblasts (OASF) was found to be 30-fold higher than in human foreskin fibroblasts (HFF). BCP crystals increased mPGES1 expression fourfold in HFF, but not in OASF. EP4 expression was downregulated twofold by BCP crystals in OASF, but not in HFF. Exogenous PGE(2) also downregulated EP4 expression; this effect was blocked by co-administration of L-161,982, a selective EP4 antagonist. While administration of exogenous PGE(2) significantly upregulated mPGES1 expression in OASF, mPGES1 expression was threefold higher in the OASF treated with BCP crystals and PGE(2) as compared with OASF treated with PGE(2) alone. The differing effects of BCP crystals on mPGES1 expression in HFF and OASF may be explained by BCP crystal-induced EP4 downregulation in OASF, likely mediated via PGE(2). These data underline the complexity of the pathways regulating PGE(2) synthesis and suggest the existence of a compensatory mechanism whereby mPGES1 expression can be diminished, potentially reducing the stimulus for further PGE(2) production.
    Osteoarthritis and Cartilage 11/2008; 17(5):686-92. · 4.26 Impact Factor
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    ABSTRACT: Despite aspirin's established role in the treatment of atherosclerotic vascular disease, considerable controversy exists regarding its most effective dosing strategy. In a retrospective observational study, we examined the relation between prescribed aspirin dose (<162 mg vs > or =162 mg/day aspirin) and clinical outcome in 4,589 placebo-treated patients enrolled in the Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial over a median follow-up of 366 days. Standard Cox regression analysis was employed because propensity analysis was not feasible. Compared with lower aspirin doses, higher doses were associated with lower unadjusted all-cause mortality (2.9 vs 1.6%, respectively; log rank chi-square 8.6, p = 0.0034). Higher aspirin dose remained independently predictive of lower all-cause mortality in a multivariable Cox proportional hazards model (hazard ratio 0.64, 95% confidence interval 0.42 to 0.97, p = 0.037). However, there was no significant difference in the incidence of the composite endpoint death, nonfatal myocardial infarction, or nonfatal stroke (6.1% vs 6.2%, p = 0.74). Higher aspirin dose was a significant independent predictor of any (hazard ratio 1.32, 95% confidence interval 1.12 to 1.55, p = 0.001) but not serious bleeding. In conclusion, our findings suggest that aspirin doses of > or =162 mg/day may be more beneficial than those <162 mg/day at preventing death.
    The American journal of cardiology 11/2008; 102(10):1285-90. · 3.58 Impact Factor

Publication Stats

6k Citations
1,525.01 Total Impact Points

Institutions

  • 1995–2013
    • University College Dublin
      • • School of Medicine & Medical Science
      • • School of Biomolecular and Biomedical Science
      Dublin, L, Ireland
  • 1996–2010
    • Royal College of Surgeons in Ireland
      • • Department of Clinical Pharmacology
      • • Department of Molecular and Cellular Therapeutics
      • • Department of Pharmaceutical & Medicinal Chemistry
      Dublin, Leinster, Ireland
  • 2007
    • Massachusetts General Hospital
      • Division of Cardiology
      Boston, MA, United States
  • 2005
    • Royal College of Surgeons of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 2004–2005
    • National Institute on Aging
      • Laboratory of Clinical Investigation (LCI)
      Baltimore, MD, United States
    • Pennsylvania State University
      • Department of Engineering Science and Mechanics
      University Park, MD, United States
    • National University of Ireland, Galway
      Gaillimh, Connaught, Ireland
  • 2002–2005
    • St. James's Hospital
      Dublin, Leinster, Ireland
    • Hospital of the University of Pennsylvania
      • Department of Pharmacology
      Philadelphia, PA, United States
    • Trinity College
      Hartford, Connecticut, United States
  • 2003
    • St Vincent's University Hospital
      Dublin, Leinster, Ireland
  • 2001
    • Beaumont Hospital
      Dublin, Leinster, Ireland
  • 1996–1997
    • University of Pennsylvania
      • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 1994
    • The Adelaide and Meath Hospital Ireland
      Dublin, Leinster, Ireland
  • 1987–1992
    • Vanderbilt University
      • • Division of Clinical Pharmacology
      • • Department of Pharmacology
      Nashville, MI, United States