The NLRP3 Inflammasome Inhibitor, OLT1177 (Dapansutrile), Reduces Infarct Size and Preserves Contractile Function After Ischemia Reperfusion Injury in the Mouse

Toldo, Stefano; Mauro, Adolfo G; Cutter, Zachary s; Tassell, Benjamin Van; Mezzaroma, Eleonora; Buono, Marco Giuseppe Del; Prestamburgo, Andrea; Potere, Nicola; Abbate, Antonio

doi:10.1097/fjc.0000000000000658

Cited by 90 publications

(44 citation statements)

References 14 publications

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“…and IL-18 into their active forms [18]. We and others have previously demonstrated the pivotal role of the NLRP3 inflammasome in cardiometabolic disorders, including myocardial ischemia reperfusion injury, [19][20][21][22][23] and several NLRP3 inhibitors, including the small molecule INF we recently developed, have been tested in animal model of IR injury, showing salvage of part of the myocardium at risk [24,25]. The cardioprotective role of NLRP3 inhibitors is attributable, at least in part, to their ability to modify protective pathways and redox environment of cells [24,26].…”

Section: Introductionmentioning

confidence: 99%

“…The NLRP3 inflammasome is a large multimeric protein complex which interacts with an apoptosis-associated speck-like protein including a caspase recruitment domain (ASC), thus recruiting and activating caspase-1, which in turn mediates the cleavage of inactive prointerleukin- (IL-) 1𝛽 and IL-18 into their active forms [ 18 ]. We and others have previously demonstrated the pivotal role of the NLRP3 inflammasome in cardiometabolic disorders, including myocardial ischemia reperfusion injury, [ 19 – 23 ] and several NLRP3 inhibitors, including the small molecule INF we recently developed, have been tested in animal model of IR injury, showing salvage of part of the myocardium at risk [ 24 , 25 ]. The cardioprotective role of NLRP3 inhibitors is attributable, at least in part, to their ability to modify protective pathways and redox environment of cells [ 24 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades

Penna

Aragno

Cento

et al. 2020

Oxidative Medicine and Cellular Longevity

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Inhibition of either P2Y12 receptor or the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome provides cardioprotective effects. Here, we investigate whether direct NLRP3 inflammasome inhibition exerts additive effects on myocardial protection induced by the P2Y12 receptor antagonist Ticagrelor. Ticagrelor (150 mg/kg) was orally administered to rats for three consecutive days. Then, isolated hearts underwent an ischemia/reperfusion (30 min ischemia/60 min reperfusion; IR) protocol. The selective NLRP3 inflammasome inhibitor INF (50 μM) was infused before the IR protocol to the hearts from untreated animals or pretreated with Ticagrelor. In parallel experiments, the hearts isolated from untreated animals were perfused with Ticagrelor (3.70 μM) before ischemia and subjected to IR. The hearts of animals pretreated with Ticagrelor showed a significantly reduced infarct size (IS, 49±3% of area at risk, AAR) when compared to control IR group (69±2% of AAR). Similarly, ex vivo administration of INF before the IR injury resulted in significant IS reduction (38±3% of AAR). Myocardial IR induced the NLRP3 inflammasome complex formation, which was attenuated by either INF pretreatment ex vivo, or by repeated oral treatment with Ticagrelor. The beneficial effects induced by either treatment were associated with the protective Reperfusion Injury Salvage Kinase (RISK) pathway activation and redox defence upregulation. In contrast, no protective effects nor NLRP3/RISK modulation were recorded when Ticagrelor was administered before ischemia in isolated heart, indicating that Ticagrelor direct target is not in the myocardium. Our results confirm that Ticagrelor conditioning effects are likely mediated through platelets, but are not additives to the ones achieved by directly inhibiting NLRP3.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades

Penna

Aragno

Cento

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…NLRP3 inflammasome has been fully characterized and plays an important role in MI/R injury. Reperfusion induces activation of NLRP3 inflammasome, and the resulting interleukin (IL)-1β, IL-18, and active caspase-1 are also involved in MI/R process ( Toldo et al, 2019 ). Previous studies showed that inhibition or deletion of NLRP3 inflammasome could reduce myocardial infarction size and improve cardiac function in experimental animal models ( Zuurbier et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Hydroxysafflor Yellow A Protects Against Myocardial Ischemia/Reperfusion Injury via Suppressing NLRP3 Inflammasome and Activating Autophagy

Ye¹,

Lu²,

Wang³

et al. 2020

Front. Pharmacol.

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Myocardial ischemia/reperfusion (MI/R) injury is a serious threat to human health. Hydroxysafflor yellow A (HSYA), the main water-soluble ingredient extracted from Carthami flos ( Carthamus tinctorius L.), has therapeutic potential for treating MI/R injury. However, the mechanisms of HSYA−mediated protection from MI/R injury are incompletely understood. In the present study, we investigated the effects and the underlying mechanisms of HSYA during MI/R. Adult Sprague-Dawley rats were subjected to left anterior descending artery ligation for 30 min followed by 24 h of reperfusion with or without HSYA treatment. The protective effect of HSYA was detected by 2,3,5-triphenyl tetrazolium chloride (TTC) staining, hematoxylin eosin (HE) staining, and myocardial enzymes detections. Serum levels of inflammatory factors such as TNF-α, interleukin (IL)-1β, and IL-18, were detected using ELISA kits. The expression of NLRP3 and other related proteins in the myocardium was detected by western blot and immunohistochemistry. The expression of autophagy-related proteins, including Atg5, BECN1, P62, and LC3B, was detected by western blot to evaluate the effect of HSYA on autophagy. Results showed that HSYA decreased the myocardial infarct size and attenuated the cardiac dysfunction in rats after I/R. In addition, HSYA inhibited myocardial apoptosis compared with the I/R group, decreased the levels of inflammatory cytokines in rat serum, reduced NLRP3 inflammasome expression, and induced autophagy. Mechanistically, our results demonstrated that HSYA can activate AMPK to improve autophagy and inhibit NLRP3 inflammasome by inhibiting the mTOR pathway. This work provides strong data supporting for the clinical applications of HSYA in MI/R injury.

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“…The NLRP3 inflammasome stimulates caspase 1 to unleash a second wave of GSDMD activity and the sole wave of pro-IL-1 processing [ 141 ]. Disulfiram (Antabuse) has been identified as a GSDMD inhibitor representing an attractive therapeutic approach [ 142 ], as well as, the NLRP3 inhibitor, OLT1177 (Dapansutrile) ( Table 2 ) [ 50 , 143 ]. High expression of NLRP3 has been seen in melanoma patients resistant to pembrolizumab.…”

Section: Gasdermin D and Gasdermin Ementioning

confidence: 99%

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

Santarpía

Aguilar

Chaib

et al. 2020

Cancers

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Treatment of advanced (metastatic) non-small-cell lung cancer (NSCLC) is currently mainly based on immunotherapy with antibodies against PD-1 or PD-L1, alone, or in combination with chemotherapy. In locally advanced NSCLC and in early resected stages, immunotherapy is also employed. Tumor PD-L1 expression by immunohistochemistry is considered the standard practice. Response rate is low, with median progression free survival very short in the vast majority of studies reported. Herein, numerous biological facets of NSCLC are described involving driver genetic lesions, mutations ad fusions, PD-L1 glycosylation, ferroptosis and metabolic rewiring in NSCLC and lung adenocarcinoma (LUAD). Novel concepts, such as immune-transmitters and the effect of neurotransmitters in immune evasion and tumor growth, the nascent relevance of necroptosis and pyroptosis, possible new biomarkers, such as gasdermin D and gasdermin E, the conundrum of K-Ras mutations in LUADs, with the growing recognition of liver kinase B1 (LKB1) and metabolic pathways, including others, are also commented. The review serves to charter diverse treatment solutions, depending on the main altered signaling pathways, in order to have effectual immunotherapy. Tumor PDCD1 gene (encoding PD-1) has been recently described, in equilibrium with tumor PD-L1 (encoded by PDCD1LG1). Such description explains tumor hyper-progression, which has been reported in several studies, and poises the fundamental criterion that IHC PD-L1 expression as a biomarker should be revisited.

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The NLRP3 Inflammasome Inhibitor, OLT1177 (Dapansutrile), Reduces Infarct Size and Preserves Contractile Function After Ischemia Reperfusion Injury in the Mouse

Cited by 90 publications

References 14 publications

Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades

Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades

Hydroxysafflor Yellow A Protects Against Myocardial Ischemia/Reperfusion Injury via Suppressing NLRP3 Inflammasome and Activating Autophagy

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

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