EX527 is a cell-permeable, selective inhibitor of mammalian sirtuin 1 (SIRT1; IC₅₀ = 98 nM) over SIRT2 and SIRT3 and has no effect on other histone deacetylases (HDACs; Nayagam et al.). SIRT1 is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase with roles in energy metabolism and inflammation. Studies have shown that EX527 inhibits sirtuins by forming a trimeric sirtuin complex with an NAD+-derived coproduct (Gertz M et al.).
DIFFERENTIATION
· Increases the production of oligodendrocytes from differentiating neural stem cells and neural progenitor cells in vitro (Rafalski et al.).
IMMUNOLOGY
· Restores the microvascular response during the hypoinflammatory phase in a mouse model of sepsis, and enhances the systemic innate immune response (Vachharajani et al.).
DISEASE MODELING
· Delays cyst growth in kidneys of PKD1 knockout mouse models (Zhou et al.)
DIFFERENTIATION
· Increases the production of oligodendrocytes from differentiating neural stem cells and neural progenitor cells in vitro (Rafalski et al.).
IMMUNOLOGY
· Restores the microvascular response during the hypoinflammatory phase in a mouse model of sepsis, and enhances the systemic innate immune response (Vachharajani et al.).
DISEASE MODELING
· Delays cyst growth in kidneys of PKD1 knockout mouse models (Zhou et al.)
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Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
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Resources and Publications
Publications (5)
SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome. Journal of leukocyte biology 2014 NOV
Abstract
Mechanism-based sepsis treatments are unavailable, and their incidence is rising worldwide. Deaths occur during the early acute phase of hyperinflammation or subsequent postacute hypoinflammatory phase with sustained organ failure. The acute sepsis phase shifts rapidly, and multiple attempts to treat early excessive inflammation have uniformly failed. We reported in a sepsis cell model and human sepsis blood leukocytes that nuclear NAD+ sensor SIRT1 deacetylase remodels chromatin at specific gene sets to switch the acute-phase proinflammatory response to hypoinflammatory. Importantly, SIRT1 chromatin reprogramming is reversible, suggesting that inhibition of SIRT1 might reverse postacute-phase hypoinflammation. We tested this concept in septic mice, using the highly specific SIRT1 inhibitor EX-527, a small molecule that closes the NAD+ binding site of SIRT1. Strikingly, when administered 24 h after sepsis, all treated animals survived, whereas only 40% of untreated mice survived. EX-527 treatment reversed the inability of leukocytes to adhere at the small intestine MVI, reversed in vivo endotoxin tolerance, increased leukocyte accumulation in peritoneum, and improved peritoneal bacterial clearance. Mechanistically, the SIRT1 inhibitor restored repressed endothelial E-selectin and ICAM-1 expression and PSGL-1 expression on the neutrophils. Systemic benefits of EX-527 treatment included stabilized blood pressure, improved microvascular blood flow, and a shift toward proimmune macrophages in spleen and bone marrow. Our findings reveal that modifying the SIRT1 NAD+ axis may provide a novel way to treat sepsis in its hypoinflammatory phase.
Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nature cell biology 2013 JUN
Abstract
Oligodendrocytes-the myelin-forming cells of the central nervous system-can be regenerated during adulthood. In adults, new oligodendrocytes originate from oligodendrocyte progenitor cells (OPCs), but also from neural stem cells (NSCs). Although several factors supporting oligodendrocyte production have been characterized, the mechanisms underlying the generation of adult oligodendrocytes are largely unknown. Here we show that genetic inactivation of SIRT1, a protein deacetylase implicated in energy metabolism, increases the production of new OPCs in the adult mouse brain, in part by acting in NSCs. New OPCs produced following SIRT1 inactivation differentiate normally, generating fully myelinating oligodendrocytes. Remarkably, SIRT1 inactivation ameliorates remyelination and delays paralysis in mouse models of demyelinating injuries. SIRT1 inactivation leads to the upregulation of genes involved in cell metabolism and growth factor signalling, in particular PDGF receptor α (PDGFRα). Oligodendrocyte expansion following SIRT1 inactivation is mediated at least in part by AKT and p38 MAPK-signalling molecules downstream of PDGFRα. The identification of drug-targetable enzymes that regulate oligodendrocyte regeneration in adults could facilitate the development of therapies for demyelinating injuries and diseases, such as multiple sclerosis.
Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. The Journal of clinical investigation 2013 JUL
Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 and is characterized by the development of multiple bilateral renal cysts that replace normal kidney tissue. Here, we used Pkd1 mutant mouse models to demonstrate that the nicotinamide adenine dinucleotide-dependent (NAD-dependent) protein deacetylase sirtuin 1 (SIRT1) is involved in the pathophysiology of ADPKD. SIRT1 was upregulated through c-MYC in embryonic and postnatal Pkd1-mutant mouse renal epithelial cells and tissues and could be induced by TNF-α, which is present in cyst fluid during cyst development. Double conditional knockouts of Pkd1 and Sirt1 demonstrated delayed renal cyst formation in postnatal mouse kidneys compared with mice with single conditional knockout of Pkd1. Furthermore, treatment with a pan-sirtuin inhibitor (nicotinamide) or a SIRT1-specific inhibitor (EX-527) delayed cyst growth in Pkd1 knockout mouse embryonic kidneys, Pkd1 conditional knockout postnatal kidneys, and Pkd1 hypomorphic kidneys. Increased SIRT1 expression in Pkd1 mutant renal epithelial cells regulated cystic epithelial cell proliferation through deacetylation and phosphorylation of Rb and regulated cystic epithelial cell death through deacetylation of p53. This newly identified role of SIRT1 signaling in cystic renal epithelial cells provides the opportunity to develop unique therapeutic strategies for ADPKD.
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