1.Finding Potent Sirt Inhibitor in Coffee: Isolation, Confirmation and Synthesis of Javamide-II (N-Caffeoyltryptophan) as Sirt1/2 Inhibitor.
Park JB1. PLoS One. 2016 Mar 17;11(3):e0150392. doi: 10.1371/journal.pone.0150392. eCollection 2016.
Recent studies suggest that Sirt inhibition may have beneficial effects on several human diseases such as neurodegenerative diseases and cancer. Coffee is one of most popular beverages with several positive health effects. Therefore, in this paper, potential Sirt inhibitors were screened using coffee extract. First, HPLC was utilized to fractionate coffee extract, then screened using a Sirt1/2 inhibition assay. The screening led to the isolation of a potent Sirt1/2 inhibitor, whose structure was determined as javamide-II (N-caffeoyltryptophan) by NMR. For confirmation, the amide was chemically synthesized and its capacity of inhibiting Sirt1/2 was also compared with the isolated amide. Javamide-II inhibited Sirt2 (IC50; 8.7μM) better than Sirt1(IC50; 34μM). Since javamide-II is a stronger inhibitor for Sirt2 than Sirt1. The kinetic study was performed against Sirt2. The amide exhibited noncompetitive Sirt2 inhibition against the NAD+ (Ki = 9.
2.Nicotinamide impairs entry into and exit from meiosis I in mouse oocytes.
Riepsamen A1, Wu L2, Lau L1, Listijono D1, Ledger W1, Sinclair D3, Homer H1. PLoS One. 2015 May 4;10(5):e0126194. doi: 10.1371/journal.pone.0126194. eCollection 2015.
Following exit from meiosis I, mammalian oocytes immediately enter meiosis II without an intervening interphase, accompanied by rapid reassembly of a bipolar spindle that maintains condensed chromosomes in a metaphase configuration (metaphase II arrest). Here we study the effect of nicotinamide (NAM), a non-competitive pan-sirtuin inhibitor, during meiotic maturation in mouse oocytes. Sirtuins are a family of seven NAD+-dependent deacetylases (Sirt1-7), which are involved in multiple cellular processes and are emerging as important regulators in oocytes and embryos. We found that NAM significantly delayed entry into meiosis I associated with delayed accumulation of the Cdk1 co-activator, cyclin B1. GVBD was also inhibited by the Sirt2-specific inhibitor, AGK2, and in a very similar pattern to NAM, supporting the notion that as in somatic cells, NAM inhibits sirtuins in oocytes. NAM did not affect subsequent spindle assembly, chromosome alignment or the timing of first polar body extrusion (PBE).
3.Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model.
Zhao T, Alam HB, Liu B, Bronson RT, Nikolian VC, Wu E, Chong W1, Li Y. Curr Mol Med. 2015;15(7):634-41.
BACKGROUND: Seven isoforms of histone deacetylase Class III have been reported - Sirtuin (SIRT) 1-7. We recently demonstrated that EX-527, an inhibitor of SIRT1, reduces mortality in a mouse model of lethal-cecal-ligationand- puncture (CLP)-induced septic shock. Our present study was aimed at determining whether selective inhibition of SIRT2, with AGK2, would decrease animal death and attenuate the inflammatory response in a septic model.
4.SIRT2 mediates oxidative stress-induced apoptosis of differentiated PC12 cells.
Nie H1, Hong Y, Lu X, Zhang J, Chen H, Li Y, Ma Y, Ying W. Neuroreport. 2014 Jun 11. [Epub ahead of print]
Sirtuin 2 (SIRT2) is a member of the sirtuin family. Previous studies have suggested that SIRT2 mediates the cell death in models of Parkinson's disease and Huntington's disease. However, the role of SIRT2 in oxidative stress-induced cell death has remained unclear. In this study, we investigated the roles of SIRT2 in oxidative stress-induced cell death using differentiated PC12 cells as a cell model. We found that H2O2 induced a significant increase in the SIRT2 level in the cells. Both SIRT2 silencing and the SIRT2 inhibitor AGK2 significantly decreased H2O2-induced apoptosis, partially by inhibiting caspase-3 activation. We further found that silencing of SIRT2 led to decreased reactive oxygen species levels in the H2O2-treated cells. Collectively, our observations have suggested that SIRT2 plays a significant role in oxidative stress-induced cell death.