The Selective Sirtuin 1 Activator SRT2104 Reduces Endotoxin-Induced Cytokine Release and Coagulation Activation in Humans*

Meer, Anne Jan van der; Scicluna, Brendon P.; Moerland, Perry D.; Lin, Jiang; Jacobson, Eric; Vlasuk, George P.; Poll, Tom van der

doi:10.1097/ccm.0000000000000949

Cited by 54 publications

(40 citation statements)

References 10 publications

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“…This appears to be linked to changes in bioenergetics that occur in tolerized cells [52]. Treatment with a SIRT1 activator reduces production of TNF-a and IL-12p40 in response to LPS injection in mice [116] and IL-6 and IL-8 after LPS injection in humans [117], supporting these results.…”

Section: Metabolic Changes During Lps Tolerancementioning

confidence: 63%

Molecular mechanisms of innate memory and tolerance to LPS

Seeley

Ghosh

2016

Journal of Leukocyte Biology

293

246

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LPS is a potent trigger of macrophage-mediated inflammation. However, prolonged exposure to LPS induces a state of tolerance that reprograms the inflammatory response, resulting in reduced inflammatory cytokine production in vitro and in vivo. Recent evidence suggests that LPS tolerance also increases the expression of a subset of genes that may protect animals from systemic infection while they are in the tolerized state. However, a molecular basis for these selective changes in inflammatory gene expression during LPS tolerance has remained elusive. In this review, we discuss the molecular mechanisms that may account for these effects, focusing on changes in LPS signaling, epigenetic markers, and chromatin remodeling that may be responsible for cellular memory and physiologic changes that comprise the LPS tolerance phenomenon.

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Section: Metabolic Changes During Lps Tolerancementioning

confidence: 63%

Molecular mechanisms of innate memory and tolerance to LPS

Seeley

Ghosh

2016

Journal of Leukocyte Biology

293

246

View full text Add to dashboard Cite

show abstract

“…Both SIRT1 activators have been shown to improve healthspan in mice, reducing inflammation and protecting from neurodegeneration (Hubbard and Sinclair, 2014). According to one clinical study, SRT2104 can reduce the serum levels of interleukin-6 and C-reactive protein induced by intravenous injection of lipopolysaccharide (van der Meer et al, 2015). Additional data on SRT2104 effects on human health will likely be reported in the near future.…”

Section: Resveratrol and Other Sirt1 Activatorsmentioning

confidence: 99%

Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential

et al. 2019

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“…SIRT1 deacetylates P53 and thereby inactivates P53-triggered transcription of its downstream genes (Vaziri et al 2001, Cheng et al 2003, Kim et al 2007. Although P53 was reported to participate in the pathogenesis of DM and a few of its complications (Deshpande et al 2013, Tang et al 2014, Kung & Murphy 2016, Li et al 2016, Su et al 2017, little was known for its role in diabetic vasculopathy. The pioneer work by Orimo and coworkers showed that high glucose (HG) resulted in hyperacetylation of P53 in HUVECs, the effect of which led to endothelial dysfunction (Orimo et al 2009).…”

Section: Journal Of Endocrinologymentioning

confidence: 99%

SRT2104 attenuates diabetes-induced aortic endothelial dysfunction via inhibition of P53

Zhou

et al. 2018

Journal of Endocrinology

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Endothelial dysfunction contributes to diabetic macrovascular complications. Sirtuin 1 (SIRT1) protects against diabetic vasculopathy. SRT2104 is a novel SIRT1 activator and was not previously studied for its effects on diabetes-induced aortic endothelial dysfunction. Additionally, whether or to what extent deacetylation of P53, a substrate of SIRT1, is required for the effects of SIRT1 activation was unclear, given the fact that SIRT1 has multiple targets. Moreover, little was known about the pathogenic role of P53 in diabetes-induced aortic injury. To these ends, diabetes was induced by streptozotocin in C57BL/6 mice. The diabetic mice developed enhanced aortic contractility, oxidative stress, inflammation, P53 hyperacetylation and a remarkable decrease in SIRT1 protein, the effects of which were rescued by SRT2104. In HG-treated endothelial cells (ECs), siRNA and SRT2104 produced similar effects on the induction of SIRT1 and the inhibition of P53 acetylation, oxidative stress and inflammation. Interestingly, SRT2104 failed to further enhance these effects in the presence of siRNA. Moreover, P53 activation by nutlin3a completely abolished SRT2104's protection against HG-induced oxidative stress and inflammation. Further, forced activation of P53 by nutlin3a increased aortic contractility in the healthy mice and generated endothelial oxidative stress and inflammation in both the normal glucose-cultured ECs and the aortas of the healthy mice. Collectively, the present study demonstrates that P53 deacetylation predominantly mediates SRT2104's protection against diabetes-induced aortic endothelial dysfunction and highlights the pathogenic role of P53 in aortic endothelial dysfunction.

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The Selective Sirtuin 1 Activator SRT2104 Reduces Endotoxin-Induced Cytokine Release and Coagulation Activation in Humans*

Abstract: This is the first human study to demonstrate biological anti-inflammatory and anticoagulant responses consistent with the activation of sirtuin 1 by a small molecule.

Cited by 54 publications

References 10 publications

Molecular mechanisms of innate memory and tolerance to LPS

Molecular mechanisms of innate memory and tolerance to LPS

Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential

SRT2104 attenuates diabetes-induced aortic endothelial dysfunction via inhibition of P53

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