Gastrointestinal safety of nitric oxide–derived aspirin is related to inhibition of ICE-like cysteine proteases in rats

Fiorucci, Stefano; Antonelli, Elisabetta; Santucci, Luca; Morelli, Olivia; Miglietti, M.; Federici, Barbara; Mannucci, Roberta; Soldato, Piero Del; Morelli, Antonio

doi:10.1016/s0016-5085(99)70012-0

Cited by 148 publications

(158 citation statements)

References 56 publications

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“…Interestingly, NO can also modulate the actions of macrophage-derived cytokines on target cells. For example, Fiorucci et al (1999) demonstrated that administration of aspirin to rats resulted in TNFα-dependent apoptosis of cells in the gastric mucosa. They further demonstrated that a NO-releasing aspirin derivative could markedly attenuate the apoptosis, and that this drug could protect gastric chief cells against damage induced by TNF through cGMP-dependent and independent mechanisms .…”

Section: Macrophagesmentioning

confidence: 99%

Nitric oxide as a regulator of inflammatory processes

Wallace

2005

Mem. Inst. Oswaldo Cruz

117

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Section: Macrophagesmentioning

confidence: 99%

Nitric oxide as a regulator of inflammatory processes

Wallace

2005

Mem. Inst. Oswaldo Cruz

117

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“…Although NO-NSAIDs spare the gastric mucosa, they inhibit prostaglandin generation and exert powerful antiapoptotic and antiinflammatory effects. Indeed, preliminary animal studies indicate that NO-NSAIDs are more effective than conventional NSAIDs in reducing inflammation and pain in arthritic rats (17,19,20). Previous studies from our laboratory have demonstrated that, similar to conventional NO donors, NO-releasing NSAIDs inhibit apoptotic pathways by causing the S-nitrosylation/inactivation of effector caspases, such as caspase 3 (20).…”

Section: Il-1␤ Converting Enzyme Is a Target For Nitricmentioning

confidence: 99%

“…We first tested whether this compound had any effect on cell viability. To ascertain this point, PBMC-derived monocytes were incubated with no agent, LPS alone, or LPS in combination with increasing concentrations, 1-200 M, of NCX-4016 or NCX-4017 for 24 h and cell viability assessed through the analysis of propidium iodide stained nuclei at flow cytometry (16,17). Briefly, macrophages were suspended in 0.1 M citrate buffer (pH 7.2) containing 0.1% Triton X-100 and 20 g/ml propidium iodide incubated at 37°C for 30 min and fluorescence intensity measured at 515/620 nm wavelength pair using a flow cytometer analyzer (Beckman-Coulter, Fullerton, CA).…”

Section: Stimulation Of Cytokine Production By Pbmc-derived Monocytesmentioning

confidence: 99%

“…ICE-like protease activity, YVADase activity, was assessed by measuring the proteolytic cleavage of fluorogenic substrates YVAD.AMC according to previous published methods (17,23). In brief, after incubation with the appropriate agent, macrophages were precipitated by centrifugation, and cytosolic extracts were prepared by repeated freezing and thawing in 300 l extraction buffer (12.5 mM Tris, pH 7.0, 1 mM DTT, 0.125 mM EDTA, 5% glycerol, 1 mM PMSF, 1 g/ml leupeptin, 1 g/ml pepstatin, and 1 g/ml aprotinin).…”

Section: Ice/caspase-1-like (Yvadase) Activitymentioning

confidence: 99%

“…Fluorescent AMC formation was measured at excitation 360 nm, emission 460 nm using a Hitachi 2000 fluorometer (Hitachi, Milan, Italy). A standard curve was constructed using AMC as standard and human recombinant ICE as previously described (17,23). Protein content was analyzed using the Bio-Rad assay (Bio-Rad Laboratories, Hercules, CA).…”

Section: Ice/caspase-1-like (Yvadase) Activitymentioning

confidence: 99%

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IL-1β Converting Enzyme Is a Target for Nitric Oxide-Releasing Aspirin: New Insights in the Antiinflammatory Mechanism of Nitric Oxide-Releasing Nonsteroidal Antiinflammatory Drugs

Fiorucci

Santucci

Cirino

et al. 2000

The Journal of Immunology

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Caspase-1, the IL-1β converting enzyme (ICE), is required for intracellular processing/maturation of IL-1β and IL-18. NO releasing nonsteroidal antiinflammatory drugs (NSAIDs) are a new class of NSAID derivatives that spare the gastric mucosa. Here, we tested the hypothesis that NCX-4016, a NO-aspirin derivative, inhibits proinflammatory cytokine release from endotoxin (LPS)-challenged monocytes. Our results demonstrated that exposing LPS-stimulated human monocytes to NCX-4016 resulted in a 40–80% inhibition of IL-1β, IL-8, IL-12, IL-18, IFN-γ, and TNF-α release with an EC50 of 10–20 μM for IL-1β and IL-18. Incubating LPS-primed monocytes with NCX-4016 resulted in intracellular NO formation as assessed by measuring nitrite/nitrate, intracellular cGMP concentration, and intracellular NO formation. Exposing LPS-stimulated monocytes to aspirin or celecoxib caused a 90% inhibition of prostaglandin E2 generation but had no effect on cytokine release. NCX-4016, similar to the NO donor S-nitroso-N-acetyl-d-l-penicillamine, inhibited caspase-1 activity with an EC50 of ≈20 μM. The inhibition of caspase-1 by NCX-4016 was reversible by the addition of DTT, which is consistent with S-nitrosylation as the mechanism of caspase-1 inhibition. NCX-4016, but not aspirin, prevented ICE activation as measured by assessing the release of ICE p20 subunit. IL-18 immunoneutralization resulted in a 60–80% reduction of IL-1β, IL-8, IFN-γ, and TNF-α release from LPS-stimulated monocytes. Taken together, these data indicate that incubating human monocytes with NCX-4016 causes intracellular NO formation and suppresses IL-1β and IL-18 processing by inhibiting caspase-1 activity. Caspase-1 inhibition is a new, cycloxygenase-independent antiinflammatory mechanism of NO-aspirin.

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NO and NO Donors

Cai

Wang

Holder

2005

Nitric Oxide Donors

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Nitric oxide (NO), a magic free radical gas molecule, has been shown to be involved in numerous physiological and pathophysiological processes. Among its diverse functions, NO has been implicated in the relaxation of vascular smooth muscle, the inhibition of platelet aggregation, neurotransmission (Viagra reverses impotence by enhancing an NO-stimulated pathway), and immune regulation [1]. It was named the molecule of the year in 1992 by Science and was the subject of the Nobel Prize in 1998. NO has limited solubility in water (2-3 mM), and it is unstable in the presence of various oxidants. This makes it difficult to introduce as such into biological systems in a controlled or specific fashion. Consequently, the development of chemical agents that release NO is important if we are to target its bioeffector roles to specific cell types for biological and pharmacological applications. Based on our comprehensive review of NO donors [2], this chapter focuses on recent progress and current trends in NO donor development and novel applications which are not covered by the following chapters.

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Gastrointestinal safety of nitric oxide–derived aspirin is related to inhibition of ICE-like cysteine proteases in rats

Cited by 148 publications

References 56 publications

Nitric oxide as a regulator of inflammatory processes

Nitric oxide as a regulator of inflammatory processes

IL-1β Converting Enzyme Is a Target for Nitric Oxide-Releasing Aspirin: New Insights in the Antiinflammatory Mechanism of Nitric Oxide-Releasing Nonsteroidal Antiinflammatory Drugs

NO and NO Donors

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