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1.  Milk-derived bioactive peptides inhibit human endothelial-monocyte interactions via PPAR-γ dependent regulation of NF-κB 
Background
Milk-derived bioactive peptides retain many biological properties and have therapeutic effects in cardiovascular disorders such as atherosclerosis. Under inflammatory conditions the expression of endothelial cells adhesion molecules is induced, increasing monocyte adhesion to human vessel wall, a critical step in the pathogenesis of atherosclerosis. In the present work we explored the effects of milk-derived bioactive peptides on the expression of the inflammatory phenotype of human endothelial cells and their effects on monocyte adherence to endothelial cells.
Results
Treatment of endothelial cells with milk-derived hydrolysate inhibited their production of inflammatory proteins MCP-1 and IL-8 and expression of VCAM-1, ICAM-1 and E-selectin. Milk derived hydrolysate also attenuated the adhesion of human monocytes to activated endothelial cells. The effect was similar to that obtained in endothelial cells treated with troglitazone, a ligand of peroxisome proliferators-activator receptor-gamma (PPAR-γ). PPAR-γ is a transcription factor which when activated antagonises the pro-inflammatory capability of nuclear factor κB (NF-κB). We further examined whether the effects of milk-derived hydrolysates on endothelial cells may be mediated through NF-κB activation via a PPAR-γ dependent mechanism. The specific PPAR-γ inhibitor, GW9662 blocked the effects of the hydrolysate on the NF-κB-mediated chemokines and adhesion molecules expression in endothelial cells.
Conclusions
These results suggest that milk-derived bioactive peptides work as anti-atherogenic agents through the inhibition of endothelial-dependent adhesive interactions with monocytes by inhibiting the NF-κB pathway through a PPAR-γ dependent mechanism.
Electronic supplementary material
The online version of this article (doi:10.1186/s12950-014-0044-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12950-014-0044-1
PMCID: PMC4308943  PMID: 25632270
Inflammation; Atherosclerosis; Milk-derived bioactive peptides; NF-κB; PPAR-γ
2.  Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo 
Journal of Clinical Investigation  2001;108(4):585-590.
The clinical use of doxorubicin, an anthracycline chemotherapeutic agent, is limited by cardiotoxicity, particularly when combined with herceptin, an antibody that blocks the HER2 receptor. Doxorubicin induces cyclooxygenase–2 (COX-2) activity in rat neonatal cardiomyocytes. This expression of COX-2 limits doxorubicin-induced cardiac cell injury, raising the possibility that the administration of a prostaglandin may protect the heart during the in vivo administration of doxorubicin. Doxorubicin (15 mg/kg) administered to adult male Sprague Dawley rats induced COX-2 expression and activity in cardiac tissue. Prostacyclin generation measured as the excretion of 2,3-dinor-6-keto-PGF1α also increased, and this was blocked by a COX-2 inhibitor, SC236. In contrast, administration of a COX-1 inhibitor SC560 at a dose that reduced serum thromboxane B2 by more than 80% did not prevent the doxorubicin-induced increase in prostacyclin generation. Doxorubicin increased cardiac injury, detected as a rise in plasma cardiac troponin T, serum lactate dehydrogenase, and cardiomyocyte apoptosis; this was aggravated by coadministration of SC236 but not SC560. The degree of injury in animals treated with a combination of doxorubicin and SC236 was attenuated by prior administration of the prostacyclin analogue iloprost. These data raise the possibility of protecting the heart during the administration of doxorubicin by prior administration of prostacyclin.
PMCID: PMC209394  PMID: 11518732
3.  Historical Lessons in Translational Medicine: Cyclooxygenase Inhibition and P2Y12 Antagonism 
Circulation research  2013;112(1):174-194.
The development of drugs that inhibit platelets has been driven by a combination of clinical insights, fundamental science and sheer luck. The process has evolved as the days of stumbling upon therapeutic gems like aspirin have long passed and have been replaced by an arduous process where a drug is designed to target a specific protein implicated in a well-characterized pathophysiological process. Or so we would like to believe. The development of antiplatelet therapy illustrates the importance of understanding the mechanisms of disease and the pharmacology of the compounds we develop, coupled with careful clinical experimentation and observation. And yes, still, a fair bit of luck.
doi:10.1161/CIRCRESAHA.111.300271
PMCID: PMC3572712  PMID: 23287454
Platelet; prostaglandin; aspirin
5.  Macrophage PPAR gamma Co-activator-1 alpha participates in repressing foam cell formation and atherosclerosis in response to conjugated linoleic acid 
EMBO Molecular Medicine  2013;5(9):1443-1457.
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.
doi:10.1002/emmm.201302587
PMCID: PMC3799497  PMID: 23964012
atherosclerosis regression; conjugated linoleic acid; foam cell formation; PGC-1α
6.  Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer 
BMC Cancer  2009;9:207.
Background
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.
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 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 μM (selective COX-2 inhibitor) for 24 hours (p = 0.02), an effect abrogated by co-incubation with PGE2 (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 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 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 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.
doi:10.1186/1471-2407-9-207
PMCID: PMC2714158  PMID: 19558693
7.  The effect of different strains of Helicobacter pylori on platelet aggregation 
BACKGROUND AND AIMS:
Helicobacter pylori is the major causative agent in peptic ulcer disease and is strongly implicated in the development of gastric cancer. It has also been linked, less strongly, to cardiovascular disease. The mechanisms by which certain strains of H pylori induce platelet aggregation through interactions with platelet glycoprotein Ib have been previously described.
METHODS:
In the present study, 21 different strains of H pylori, varying in their vacuolating toxin gene, cytotoxic-associated gene A status and other pathogenicity factors, were tested for their ability to induce platelet aggregation.
RESULTS:
Ten of the 21 strains induced platelet aggregation, a response that appeared to be independent of their vacuolating toxin gene and cytotoxic-associated gene A status.
CONCLUSIONS:
Platelet aggregation has been suggested to be one of the possible mechanisms involved in the effects on the cardiovascular system induced by H pylori. Our results suggest that any putative role H pylori plays in cardiovascular disease may be strain dependent. Further work to identify the H pylori factors involved in induction of platelet aggregation may allow for identification of ‘higher risk’ strains for cardiovascular disease.
PMCID: PMC2658119  PMID: 17571170
Cardiovascular disease; H pylori; Platelet aggregation
8.  Elevated white cell count in acute coronary syndromes: relationship to variants in inflammatory and thrombotic genes 
BMC Medical Genetics  2004;5:13.
Background
Elevated white blood cell counts (WBC) in acute coronary syndromes (ACS) increase the risk of recurrent events, but it is not known if this is exacerbated by pro-inflammatory factors. We sought to identify whether pro-inflammatory genetic variants contributed to alterations in WBC and C-reactive protein (CRP) in an ACS population.
Methods
WBC and genotype of interleukin 6 (IL-6 G-174C) and of interleukin-1 receptor antagonist (IL1RN intronic repeat polymorphism) were investigated in 732 Caucasian patients with ACS in the OPUS-TIMI-16 trial. Samples for measurement of WBC and inflammatory factors were taken at baseline, i.e. Within 72 hours of an acute myocardial infarction or an unstable angina event.
Results
An increased white blood cell count (WBC) was associated with an increased C-reactive protein (r = 0.23, p < 0.001) and there was also a positive correlation between levels of β-fibrinogen and C-reactive protein (r = 0.42, p < 0.0001). IL1RN and IL6 genotypes had no significant impact upon WBC. The difference in median WBC between the two homozygote IL6 genotypes was 0.21/mm3 (95% CI = -0.41, 0.77), and -0.03/mm3 (95% CI = -0.55, 0.86) for IL1RN. Moreover, the composite endpoint was not significantly affected by an interaction between WBC and the IL1 (p = 0.61) or IL6 (p = 0.48) genotype.
Conclusions
Cytokine pro-inflammatory genetic variants do not influence the increased inflammatory profile of ACS patients.
doi:10.1186/1471-2350-5-13
PMCID: PMC425582  PMID: 15171792
Inflammation; acute coronary syndromes; White cell count; interleukin 1 receptor antagonist; interleukin 6

Results 1-8 (8)