Mechanistic Insights into Cyclooxygenase Irreversible Inactivation by Aspirin

Tosco, Paolo; Lazzarato, Loretta

doi:10.1002/cmdc.200800438

Cited by 32 publications

(29 citation statements)

References 33 publications

(44 reference statements)

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“…Aspirin is more reactive than other salicylates and is known to irreversibly acylate proteins (e.g., COX-1 and fibrinogen). 34,35 It is possible that the loss of carboxypeptidase activity induced by aspirin may also be due to irreversible TAFIa acylation. The molecular mechanisms of TAFIa inhibition by various salicylates require further study.…”

Section: Discussionmentioning

confidence: 99%

Alternative Mechanism of Aspirin in Anti-Thrombotic Therapy: Inhibition of Thrombin Activatable Fibrinolysis Inhibitor

Soo¹,

An²,

Greenfield³

2012

Bulletin of the Korean Chemical Society

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The use of aspirin is widely recommended for the prevention of heart attacks owing to its ability to inhibit platelet activation by irreversibly blocking cyclooxygenase 1. However, aspirin also affects the fibrinolytic and hemostatic pathways by mechanisms that are not well understood, causing severe hemorrhagic complications. Here, we investigated the ability of aspirin and aspirin metabolites to inhibit thrombin-activatable fibrinolysis inhibitor (TAFI), the major inhibitor of plasma fibrinolysis. TAFI is activated via proteolytic cleavage by the thrombin-thrombomodulin complex to TAFIa, a carboxypeptidase B-like enzyme. TAFIa modulates fibrinolysis by removing the C-terminal arginine and lysine residues from partially degraded fibrin, which in turn inhibits the binding of plasminogen to fibrin clots. Aspirin and its major metabolites, salicylic acid, gentisic acid, and salicyluric acid, inhibit TAFIa carboxypeptidase activity. Salicyluric acid effectively blocks activation of TAFI by thrombin-thrombomodulin; however, salicylates do not inhibit carboxypeptidase N or pancreatic carboxypeptidase B. Aspirin and other salicylates accelerated the dissolution of fibrin clots and reduced thrombus formation in an in vitro model of fibrinolysis. Inhibition of TAFI represents a novel hemostatic mechanism that contributes to aspirin's therapy-associated antithrombotic activity and hemorrhagic complications.

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Section: Discussionmentioning

confidence: 99%

Alternative Mechanism of Aspirin in Anti-Thrombotic Therapy: Inhibition of Thrombin Activatable Fibrinolysis Inhibitor

Soo¹,

An²,

Greenfield³

2012

Bulletin of the Korean Chemical Society

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Section: Acetyltransferasesmentioning

confidence: 99%

“…This nonenzymatic acetylation results in the irreversible inhibition of COX1 [45]. COX2, an isoform of COX1, is reported to get acetylated in its active site Ser-516 in the same way as it binds to Ser-530 of COX1 [45]. Some reports claim that aspirin is capable of acetylating diverse cellular proteins such as human serum albumin [46], fibrinogen [47], hemoglobin [48], endothelial NOS [49], and tumor suppressor protein p53 [50] at the N ε -lysine residues, to regulate their functions [9].…”

Section: Acetyltransferasesmentioning

confidence: 99%

Comparison of Protein Acetyltransferase Action of CRTAase with the Prototypes of HAT

Ponnan

Kumar

Singh

et al. 2014

The Scientific World Journal

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Our laboratory is credited for the discovery of enzymatic acetylation of protein, a phenomenon unknown till we identified an enzyme termed acetoxy drug: protein transacetylase (TAase), catalyzing the transfer of acetyl group from polyphenolic acetates to receptor proteins (RP). Later, TAase was identified as calreticulin (CR), an endoplasmic reticulum luminal protein. CR was termed calreticulin transacetylase (CRTAase). Our persistent study revealed that CR like other families of histone acetyltransferases (HATs) such as p300, Rtt109, PCAF, and ESA1, undergoes autoacetylation. The autoacetylated CR was characterized as a stable intermediate in CRTAase catalyzed protein acetylation, and similar was the case with ESA1. The autoacetylation of CR like that of HATs was found to enhance protein-protein interaction. CR like HAT-1, CBP, and p300 mediated the acylation of RP utilizing acetyl CoA and propionyl CoA as the substrates. The similarities between CRTAase and HATs in mediating protein acylation are highlighted in this review.

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“…19,20 Recent research has revealed that aspirin may modulate the balance between bone resorption and bone formation in ovariectomy-induced osteoporosis, and can accelerate bone repair in rodents and inhibit the differentiation and maturity of osteoclasts. [21][22][23] When inflammatory tissue exists, bone mesenchymal stem cells (BMSCs) have exhibited impaired immunoregulatory properties.…”

Section: Introductionmentioning

confidence: 99%

Guided bone regeneration with asymmetric collagen-chitosan membranes containing aspirin-loaded chitosan nanoparticles

Zhang¹,

Ma²,

Liu³

et al. 2017

IJN

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Introduction Membranes allowing the sustained release of drugs that can achieve cell adhesion are very promising for guided bone regeneration. Previous studies have suggested that aspirin has the potential to promote bone regeneration. The purpose of this study was to prepare a local drug delivery system with aspirin-loaded chitosan nanoparticles (ACS) contained in an asymmetric collagen-chitosan membrane (CCM). Methods In this study, the ACS were fabricated using different concentrations of aspirin (5 mg, 25 mg, 50 mg, and 75 mg). The drug release behavior of ACS was studied. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were used to examine the micromorphology of ACS and aspirin-loaded chitosan nanoparticles contained in chitosan-collagen membranes (ACS-CCM). In vitro bone mesenchymal stem cells (BMSCs) were cultured and critical-sized cranial defects on Sprague-Dawley rats were made to evaluate the effect of the ACS-CCM on bone regeneration. Results Drug release behavior results of ACS showed that the nanoparticles fabricated in this study could successfully sustain the release of the drug. TEM showed the morphology of the nanoparticles. SEM images indicated that the asymmetric membrane comprised a loose collagen layer and a dense chitosan layer. In vitro studies showed that ACS-CCM could promote the proliferation of BMSCs, and that the degree of differentiated BMSCs seeded on CCMs containing 50 mg of ACS was higher than that of other membranes. Micro-computed tomography showed that 50 mg of ACS-CCM resulted in enhanced bone regeneration compared with the control group. Conclusion This study shows that the ACS-CCM would allow the sustained release of aspirin and have further osteogenic potential. This membrane is a promising therapeutic approach to guiding bone regeneration.

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Mechanistic Insights into Cyclooxygenase Irreversible Inactivation by Aspirin

Cited by 32 publications

References 33 publications

Alternative Mechanism of Aspirin in Anti-Thrombotic Therapy: Inhibition of Thrombin Activatable Fibrinolysis Inhibitor

Alternative Mechanism of Aspirin in Anti-Thrombotic Therapy: Inhibition of Thrombin Activatable Fibrinolysis Inhibitor

Comparison of Protein Acetyltransferase Action of CRTAase with the Prototypes of HAT

Guided bone regeneration with asymmetric collagen-chitosan membranes containing aspirin-loaded chitosan nanoparticles

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