A SIRT2 inhibitor
AK-1 is a sirtuin 2 (SIRT2) inhibitor (IC50 = 12.5 ?M).1 It induces the formation of α-synuclein aggregates in H4 neuroglioma cells expressing α-synuclein and synphilin-1.2 AK-1 (5 ?M) decreases total cholesterol levels in Neuro2a and primary rat striatal neurons, as well as in hippocampal slice cultures.1 It increases ubiquitination of hypoxia-inducible factor-1α (HIF-1α) in A549 cells and decreases HIF-1α levels in A549, HeLa, HEK293, and HEK293T cells under hypoxic conditions when used at a concentration of 10 ?M.3 AK-1 (1 and 10 ?M in the diet) decreases the loss of rhabdomeres in the ommatidium in the UAS-Httex1p-Q93 transgenic Drosophila model of Huntington's disease.4 Dietary administration of AK-1 (500 and 1,000 ?M) prevents dopaminergic neuronal cell death in the dorsomedial cluster in the elav-GAL4 transgenic Drosophila model of Parkinson's disease.2
1.Taylor, D.M., Balabadra, U., Xiang, Z., et al.A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylaseACS Chem Biol.6(6)540-546(2011) 2.Outeiro, T.F., Kontopoulos, E., Altmann, S.M., et al.Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's diseaseScience317(5837)516-519(2007) 3.Lee, S.D., Kim, W., Jeong, J.-W., et al.AK-1, a SIRT2 inhibitor, destabilizes HIF-1α and diminishes its transcriptional activity during hypoxiaCancer Lett.373(1)138-145(2016) 4.Luthi-Carter, R., Taylor, D.M., Pallos, J., et al.SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesisProc. Natl. Acad. Sci. USA107(17)7927-7932(2010)
Cell experiment: | HEK293 cells are co-transfected with 3 μg of pGL2-PGK1-HRE-Luc and 1 μg of pCMV-β-galactosidase plasmids. Twenty-four hours later, the cells are incubated under hypoxic conditions for 24 hr in the presence of 10 μM AK-1 and then lysed with luciferase cell lysis buffer. Luciferase and β-galactosidase activities are measured using luciferin and ο-nitrophenyl-β-d-galactopyranoside, respectively, as substrates. Transfection efficiency is normalized according to β-galactosidase activity[3]. |
参考文献: [1]. Luthi-Carter R, et al. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7927-32. | |
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