Sirtuin activators

Abstract

To date, resveratrol is the most potent natural compound able to activate SIRT1, mimicking the positive effect of calorie restriction. Resveratrol might help in the treatment or prevention of obesity and in preventing the aging-related decline in heart function and neuronal loss. As resveratrol has low bioavailability and interacts with multiple molecular targets, the development of new molecules with better bioavailability and targeting sirtuin at lower concentrations is a promising field of the medicinal chemistry. New SIRT1 activators that are up to 1000 times more effective than resveratrol have recently been identified. These improve the response to insulin and increase the number and activity of mitochondria in obese mice. Human trials with a formulation of resveratrol with improved bioavailability and with a synthetic SIRT1 activator are in progress.

Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1

“…It is known that a major target of RSV is Sirt1 (33). The biological effects of RSV, including its reported effect in extending longevity in lower organisms, have been demonstrated to occur through activation of Sirt1, the NAD + -dependent histone deacetylase (18,33).…”

“…It is known that a major target of RSV is Sirt1 (33). The biological effects of RSV, including its reported effect in extending longevity in lower organisms, have been demonstrated to occur through activation of Sirt1, the NAD + -dependent histone deacetylase (18,33). We began to investigate the role of Sirt1 following hemorrhage on the basis of our findings on injury-induced alterations in the mitoscriptome expression profile, using the focused mitochondrial gene chip, RoMitochip (15,29).…”

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

“…For this reason, most HDAC inhibitors do not target sirtuins (Michan and Sinclair, 2007). However, Sirt1 and Sirt2 selective inhibitors have been identified, including Sirt1 selective inhibitors EX-S27, HR73, 2-Anilincbenzamide, and suramin derivatives; Sirt2 selective inhibitors AGK2 and adenosine mimetics; as well as the Sirt1 and 2 inhibitor cambinol (Alcain and Villalba, 2009a;Itoh et al, 2008). In addition to inhibitors, resveratrol has been identified as a Sirt1 activator (Alcain and Villalba, 2009b;Shakibaei et al, 2011;Villalba et al, 2012), and the development of additional activators is in progress (Villalba et al, 2012).…”

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

“…The majority of these studies showed that methotrexate (MTX) and leflunomide were able to induce apoptosis in vitro in a variety 1 c-kit tyrosine kinase is a mast/stem cell growth factor receptor also known as CD117 [131] 2 ZAP-70, ζ-chain-associated protein-70 and a member of the tyrosine kinase family that is normally expressed by T-cells and natural killer cells [132] 3 SIRT1 is silent mating type information regulation 2 homolog (sirtuin-1) and a deacetylating enzyme [133] 4 PAR-2, Protease-activated receptor-2 and a subfamily member related to G-protein coupled receptors that may be activated by cleavage through their extracellular domain [134] 5 NF-AT5, Nuclear factor of activated T-cells 5 belonging to the NFAT family of transcription factors [135] 6 Human umbilical vascular endothelial cells 7 Mcl-1, Induced myeloid leukemia cell differentiation protein [136] 8 Epigallocatechin-3-gallate 9 MDC, myeloid-derived cells; PDC, plasmacytoid-derived cells 10 Apaf-1, Apoptotic protease activating factor-1 11 An inhibitor of geranylgeranyl transferase [137] 12 An inhibitor of RhoA kinase [138] 1 REL1096 is the p65 (Rel A) subunit of NF-κB 2 GADD45β is the growth arrest and DNA-damage-inducible45β protein [148] 3 Putative consensus sites for the binding of miR-124a and miR-146a to the 3'-untranslated regions of cyclin-dependent kinase-2 (CDK-2) and MCP-1, respectively 4 Putative consensus site for the binding of miR-146a to the 3' untranslated region of Fas-associated factor-1 of cells pertinent to RA pathology as well as cells involved in generalized inflammation, including, T-cells, neutrophils, mast cells and macrophages. By contrast, although NSAIDS were proposed as potential apoptosis inducers [166], the NSAID, celecoxib, failed to induce apoptosis in RAFLS in vitro [171].…”