Historical Lessons in Translational Medicine

Fitzgerald, Desmond J.; FitzGerald, Garret A.

doi:10.1161/circresaha.111.300271

Cited by 36 publications

(24 citation statements)

References 177 publications

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“…Notably, considerable individual variability in platelet response and oxylipin production was observed with acute EVOO intake, consistent with variability in other platelet responsive factors (e.g. “aspirin resistance”) which have been postulated to result from differences in metabolism, sex, drug interactions and compliance failure (Fitzgerald & Fitzgerald, 2013; Rocca & Patrono, 2005). Dietary factors may also have played a role, and habitual diet assessments may have aided interpretation of this study.…”

Section: Discussionsupporting

confidence: 64%

Oleocanthal-rich extra virgin olive oil demonstrates acute anti-platelet effects in healthy men in a randomized trial

Agrawal

Melliou

et al. 2017

Journal of Functional Foods

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The phenolic profiles of extra virgin olive oils (EVOOs) may influence their cardiovascular benefits. In a randomized crossover of acute EVOO intake on platelet function, participants (n=9) consumed 40 mL of EVOO weekly. EVOOs were matched for total phenolic content and were either tyrosol-poor with 1:2 oleacein/oleocanthal (D2i0.5), or 2:1 oleacein/oleocanthal (D2i2), or predominantly tyrosol (D2i0). Ibuprofen provided a platelet inhibition control. Blood was collected pre- and 2 hr post-EVOO intake. D2i0.5 and D2i2 reduced 1 µg/mL collagen-stimulated maximum platelet aggregation (Pmax), with effects best correlated to oleocanthal intake (R=0.56, P=0.002). Total phenolic intake was independently correlated to eicosanoid production inhibition, suggesting that cyclooxygenase blockade was not responsible for the Pmax inhibition. Five participants exhibited >25% ΔPmax declines with D2i0.5 and D2i2 intake and plasma metabolomic profiles discriminated subjects by oil responsivity. Platelet responses to acute EVOO intake are associated with oil phenolic composition and may be influenced by diet.

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Section: Discussionsupporting

confidence: 64%

Oleocanthal-rich extra virgin olive oil demonstrates acute anti-platelet effects in healthy men in a randomized trial

Agrawal

Melliou

et al. 2017

Journal of Functional Foods

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“…This was established by seminal work from several laboratories notably those of Vane, Samuelsson, Roth & Majerus, Patrono and FitzGerald 20, 109-115 , and was recently the subject of the 2013 Grand Prix Scientific (Lefoulon-Delalande Foundation, Institute of France) awarded to Garret FitzGerald and Carlo Patrono. More recently, a number of studies found that low dose (considered platelet-selective) aspirin can reduce the spread of existing cancers as well as the risk of developing others, in particular adenocarcinoma of the gut, some lung cancers and breast and prostate cancer.…”

Section: Specific Lipid Families In Plateletsmentioning

confidence: 99%

Platelet Lipidomics

O'Donnell

Murphy

Watson³

2014

Circulation Research

130

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Lipids are diverse families of biomolecules that perform essential structural and signaling roles in platelets. Their formation and metabolism is tightly controlled by enzymes and signal transduction pathways, and their dysregulation leads to significant defects in platelet function and disease. Platelet activation is associated with significant changes to membrane lipids, and formation of diverse bioactive lipids that play essential roles in hemostasis. In recent years, new generation mass spectrometry analysis of lipids (termed “lipidomics”) has begun to alter our understanding of how these molecules participate in key cellular processes. While, the application of lipidomics to platelet biology is still in its infancy, seminal earlier studies have shaped our knowledge of how lipids regulate key aspects of platelet biology, including aggregation, shape change, coagulation and degranulation, as well as how lipids generated by platelets influence other cells, such as leukocytes and the vascular wall, and thus how they regulate hemostasis, vascular integrity and inflammation, as well as contribute to pathologies including arterial/deep vein thrombosis and atherosclerosis. This review will provide a brief historical perspective on the characterization of lipids in platelets, then an overview of the new generation lipidomic approaches, their recent application to platelet biology, and future perspectives for research in this area. The major platelet-regulatory lipid families, their formation, metabolism, and their role in health and disease, will be summarized.

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“…Constitutively expressed COX-1 accounts largely for formation of PGs subserving “housekeeping” functions, such as thromboxane A 2 (TxA 2 ) in hemostasis and PGE 2 and PGI 2 in the maintenance of gastroduodenal epithelial integrity. Platelets express only COX-1, and suppression of platelet COX-1–dependent TxA 2 by low-dose aspirin accounts for its cardioprotective effects (2). COX-2 is more readily regulated in its expression, especially by mitogens and cytokines, and accounts largely for elaboration of the PGE 2 and PGI 2 that mediate pain and inflammation.…”

Section: Introductionmentioning

confidence: 99%

A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood

Mazaleuskaya¹,

Lawson²,

Li³

et al. 2016

JCI Insight

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Current methods of drug screening in human blood focus on the immediate products of the affected pathway and mostly rely on approaches that lack sensitivity and the capacity for multiplex analysis. We have developed a sensitive and selective method based on ultra-performance liquid chromatography–tandem mass spectrometry to scan the effect of drugs on the bioactive eicosanoid lipidome in vitro and ex vivo. Using small sample sizes, we can reproducibly measure a broad spectrum of eicosanoids in human blood and capture drug-induced substrate rediversion and unexpected shifts in product formation. Microsomal prostaglandin E synthase-1 (mPGES-1) is an antiinflammatory drug target alternative to COX-1/-2. Contrasting effects of targeting mPGES-1 versus COX-1/-2, due to differential substrate shifts across the lipidome, were observed and can be used to rationalize and evaluate drug combinations. Finally, the in vitro results were extrapolated to ex vivo studies by administration of the COX-2 inhibitor, celecoxib, to volunteers, illustrating how this approach can be used to integrate preclinical and clinical studies during drug development.

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Historical Lessons in Translational Medicine

Cited by 36 publications

References 177 publications

Oleocanthal-rich extra virgin olive oil demonstrates acute anti-platelet effects in healthy men in a randomized trial

Oleocanthal-rich extra virgin olive oil demonstrates acute anti-platelet effects in healthy men in a randomized trial

Platelet Lipidomics

A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood

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