5-Lipoxygenase Metabolic Contributions to NSAID-Induced Organ Toxicity

Burnett, Bruce; Levy, Robert M.

doi:10.1007/s12325-011-0100-7

Cited by 50 publications

(31 citation statements)

References 162 publications

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“…Considering the involvement of both COX and LOX pathways in common inflammatory diseases, such as atherosclerosis (13, 14), abdominal aortic aneurysm (39–41), asthma (42, 43), arthritis, and inflammatory pain (13, 44, 45), dual inhibitors of both pathways are of interest (46). Concurrent blockade of mPGES-1 with inhibition of various components of the 5-LOX pathway revealed both predicted and unexpected effects on the human plasma lipidome.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…There are several human and animal studies finely reviewed to support this hypothesis [18]. 5- and 12-LOX metabolic pathways are linked to carcinogenesis [152], and altered COX and LOX metabolism of arachidonic acid are a common factor in malignancy [35].…”

Section: Discussionmentioning

confidence: 99%

“…Levels of possible side effects of NSAIDs [18]. Drug- and cell-specific inhibition of COX isoenzymes [15] and respective prostanoids results in alteration of homeostasis [7] and in promotion of proinflammatory conditions [18–22].…”

Section: Figurementioning

confidence: 99%

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Alleviating Promotion of Inflammation and Cancer Induced by Nonsteroidal Anti-Inflammatory Drugs

Kyriakopoulos¹,

Nagl

Baliou

et al. 2017

International Journal of Inflammation

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Clinical Relevance Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including aspirin are of intensive use nowadays. These drugs exert their activity via the metabolism of arachidonic acid (AA) by cyclooxygenase inhibition. Though beneficial for health in some instances, both unspecific and specific cyclooxygenase inhibitor activity interfere with AA metabolism producing also proinflammatory lipids that may promote cancer. Materials and Methods This review is based on available literature on clinical uses, biochemical investigations, molecular medicine, pharmacology, toxicity, and epidemiology-clinical studies on NSAIDs and other drugs that may be used accordingly, which was collected from electronic (SciFinder, Medline, Science Direct, and ACS among others) and library searches of books and journals. Results Relevant literature supports the notion that NDSAID use may also promote proinflammatory biochemical events that are also related to precancerous predisposition. Several agents are proposed that may be employed in immediate future to supplement and optimize treatment with NSAIDs. In this way serious side effects arising from promotion of inflammation and cancer, especially in chronic NSAID users and high risk groups of patients, could be avoided.

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“…It should be noted that AA can also be metabolized through the lipoxygenase and epoxygenase pathways, reviewed elsewhere (4), and, importantly, that NSAIDs do not block these pathways. In fact, blocking COX metabolism of AA could redirect AA down these alternative pathways and could even explain some of the negative effects of NSAID action on various tissues (10). The main focus of this review is on NSAID action through the COX/PG pathways due to the lack of literature on the influence of the lipoxygenase and epoxygenase pathways on skeletal muscle.…”

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confidence: 99%

Does an NSAID a day keep satellite cells at bay?

Mackey

2013

Journal of Applied Physiology

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Mackey AL. Does an NSAID a day keep satellite cells at bay? J Appl Physiol 115: 900-908, 2013. First published May 16, 2013 doi:10.1152/japplphysiol.00044.2013.-Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed by athletes worldwide, despite growing evidence for a negative influence on the adaptation of skeletal muscle to exercise, at least in young healthy individuals. This review focuses on the potential of NSAIDs to alter the activity of satellite cells, the muscle stem cell responsible for repair and maintenance of skeletal muscle. The signaling pathways that are potentially modified by NSAID exposure are also considered. Growth factors as well as inflammatory cells and connective tissue appear to be key factors in the response of muscle under conditions where cyclooxygenase and prostaglandin activity are blocked through NSAID ingestion or infusion. Discrepancies in the literature regarding the response of young and old individuals are addressed, where it appears that the elderly may benefit from NSAID ingestion, although this clearly requires further study. The long-term implications for the muscle of the apparent inhibitory effect of NSAIDs on satellite cells in younger individuals are not clear, and it is possible these may first become apparent with chronic use in athletes training at a high level or with advancing age. Reports of the potential for NSAIDs to alter prostaglandin and growth factor signaling provide a basis for further study of the mechanism of NSAID action on satellite cells. exercise; growth factor; muscle adaptation; NSAIDs; satellite cells SATELLITE CELLS (see Figs. 1 and 2) are a population of cells resident in adult skeletal muscle and have been proven to be essential for muscle repair (33, 67). The cycle of satellite cell activity (see Fig. 3) has been most widely studied in models of muscle injury or overload where the satellite cells are awoken from their dormant state. Briefly, the main steps involved include 1) activation to enter the cell cycle, and 2) proliferation, after which the cells either 3) undergo differentiation and fuse with a myofiber, or 4) return to quiescence (24,50,68,95). With the capacity to perform these two functions, namely repairing damaged tissue and replenishing their own cell pool, satellite cells have been ascribed the status of the muscle stem cell. While it appears that satellite cells in the muscle of elderly individuals are not as easily activated as in younger individuals (11), triggering activation and proliferation in vivo appears to be relatively easy, and many factors are now recognized as being capable of this. For example, mechanical stimuli in the form of stretch or forceful contractions, damage to the muscle, pharmacological agents, and inflammatory conditions are strong activators of satellite cells. It appears from the literature that nonsteroidal anti-inflammatory drugs (NSAIDs) can influence satellite cell activity, both directly and indirectly. This minireview will consider how NSAIDs can influence satellite cells at an...

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5-Lipoxygenase Metabolic Contributions to NSAID-Induced Organ Toxicity

Cited by 50 publications

References 162 publications

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

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

Alleviating Promotion of Inflammation and Cancer Induced by Nonsteroidal Anti-Inflammatory Drugs

Does an NSAID a day keep satellite cells at bay?

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