Small molecules inhibitors of plasminogen activator inhibitor-1 – An overview

Rouch, Anne; Vanucci-Bacqué, Corinne; Bedos‐Belval, Florence; Baltas, Michel

doi:10.1016/j.ejmech.2015.01.010

Cited by 50 publications

(37 citation statements)

References 97 publications

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“…PCB126 also upregulated plasma levels and hepatic expression of PAI-1 . Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis since this serine protease inhibitor prevents breakdown of fibrin clots (Rouch et al 2015). Nonetheless, in this study, the effect of PCBs on CVD renders more in-depth and mechanistic studies.…”

Section: Discussionmentioning

confidence: 99%

A compromised liver alters polychlorinated biphenyl-mediated toxicity

et al. 2017

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Exposure to environmental toxicants namely polychlorinated biphenyls (PCBs) is correlated with multiple health disorders including liver and cardiovascular diseases. The liver is important for both xenobiotic and endobiotic metabolism. However, the responses of an injured liver to subsequent environmental insults has not been investigated. The current study aims to evaluate the role of a compromised liver in PCB-induced toxicity and define the implications on overall body homeostasis. Male C57Bl/6 mice were fed either an amino acid control diet (CD) or a methionine-choline deficient diet (MCD) during the 12-week study. Mice were subsequently exposed to either PCB126 (4.9 mg/kg) or the PCB mixture, Arcolor1260 (20 mg/kg) and analyzed for inflammatory, calorimetry and metabolic parameters. Consistent with the literature, MCD diet-fed mice demonstrated steatosis, indicative of a compromised liver. Mice fed the MCD-diet and subsequently exposed to PCB126 showed observable wasting syndrome leading to mortality. PCB126 and Aroclor1260 exposure worsened hepatic fibrosis exhibited by the MCD groups. Interestingly, PCB126 but not Aroclor1260 induced steatosis and inflammation in CD-fed mice. Mice with liver injury and subsequently exposed to PCBs also manifested metabolic disturbances due to alterations in hepatic gene expression. Furthermore, PCB exposure in MCD-fed mice led to extra-hepatic toxicity such as upregulated circulating inflammatory biomarkers, implicating endothelial cell dysfunction. Taken together, these results indicate that environmental pollution can exacerbate toxicity caused by diet-induced liver injury which may be partially due to dysfunctional energy homeostasis. This is relevant to PCB-exposed human cohorts who suffer from alcohol or diet-induced fatty liver diseases.

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Section: Discussionmentioning

confidence: 99%

A compromised liver alters polychlorinated biphenyl-mediated toxicity

et al. 2017

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“…A number of groups have employed different methods for identification of PAI-1 inhibitors, including high throughput and in silico screening, reviewed extensively elsewhere [114, 160]. Using this methodology, Elokdah and colleagues identified Tiplaxtinin as a potent and selective PAI-1 inhibitor [161], which became one of the most studied PAI-1 inhibitors to date.…”

Section: Current Approaches To Reduce Hypofibrinolysis In Diabetesmentioning

confidence: 99%

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

Kearney

Tomlinson

Smith

et al. 2017

Cardiovasc Diabetol

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An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition.

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“…These findings outline a new medicinal potential for Annonaceous acetogenins and evidence their influence in haemostasis, as persenone-A, an analogous polyketide from avocado (Lauraceae), also showed protective effects against arterial thrombosis in vivo and anti-platelet activity39. Several other small molecule PAI-1 inhibitors displayed in vivo efficacy40 but so far only three reached phase 1 clinical trial (tiplaxtinin, PAI-749 and PAZ-417) without further progression. In this context, the benefit-risk ratio of annonacinone deserves to be evaluated.…”

Section: Discussionmentioning

confidence: 76%

Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1

Pautus

Alami

Adam

et al. 2016

Sci Rep

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Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of the tissue type and urokinase type plasminogen activators. High levels of PAI-1 are correlated with an increased risk of thrombotic events and several other pathologies. Despite several compounds with in vitro activity being developed, none of them are currently in clinical use. In this study, we evaluated a novel PAI-1 inhibitor, annonacinone, a natural product from the Annonaceous acetogenins group. Annonacinone was identified in a chromogenic screening assay and was more potent than tiplaxtinin. Annonacinone showed high potency ex vivo on thromboelastography and was able to potentiate the thrombolytic effect of tPA in vivo in a murine model. SDS-PAGE showed that annonacinone inhibited formation of PAI-1/tPA complex via enhancement of the substrate pathway. Mutagenesis and molecular dynamics allowed us to identify annonacinone binding site close to helix D and E and β-sheets 2A.

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Small molecules inhibitors of plasminogen activator inhibitor-1 – An overview

Cited by 50 publications

References 97 publications

A compromised liver alters polychlorinated biphenyl-mediated toxicity

A compromised liver alters polychlorinated biphenyl-mediated toxicity

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1

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