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10.1093/hmg/ddu010 http://scihub22266oqcxt.onion/10.1093/hmg/ddu010 C4031626!4031626 !24436303     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\24436303 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Hum+Mol+Genet 2014 ; 23 (11 ): 2995-3007 Nephropedia Template TP {{tp|p=24436303 |t=2014. A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington s disease |pdf=|usr=}}{{24436303 }} gab.com Text A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington s disease JO: Hum Mol Genet http://www.kidney.de/pget.php?&tw=1&pmid=24436303 #FOAvip Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophila melanogaster) deacetylates histones and other proteins including transcription factors. Genetically reducing, but not eliminating, Sir2 has been shown to suppress HD pathology in model organisms. To date, small molecule inhibitors of sirtuins have exhibited low potency and unattractive pharmacological and biopharmaceutical properties. Here, we show that highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) can suppress HD pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. We have validated Sir2 as the in vivo target of selisistat by showing that genetic elimination of Sir2 eradicates the effect of this inhibitor in Drosophila. The specificity of selisistat is shown by its effect on recombinant sirtuins in mammalian cells. Reduction of HD pathology by selisistat in Drosophila, mammalian cells and mouse models of HD suggests that this inhibitor has potential as an effective therapeutic treatment for human disease and may also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for HD. Twit Text FOAVip A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington s disease ????Hum Mol Genet http://www.kidney.de/pget.php?&tw=1&pmid=24436303 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=24436303 #FOAvip English Wikipedia <ref>{{Cite pmid|24436303 }}</ref> A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington s disease #MMPMID24436303 Smith MR ; Syed A ; Lukacsovich T ; Purcell J ; Barbaro BA ; Worthge SA ; Wei SR ; Pollio G ; Magnoni L ; Scali C ; Massai L ; Franceschini D ; Camarri M ; Gianfriddo M ; Diodato E ; Thomas R ; Gokce O ; Tabrizi SJ ; Caricasole A ; Landwehrmeyer B ; Menalled L ; Murphy C ; Ramboz S ; Luthi-Carter R ; Westerberg G ; Marsh JL Hum Mol Genet 2014[Jun]; 23 (11 ): 2995-3007 PMID24436303 show ga Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophila melanogaster) deacetylates histones and other proteins including transcription factors. Genetically reducing, but not eliminating, Sir2 has been shown to suppress HD pathology in model organisms. To date, small molecule inhibitors of sirtuins have exhibited low potency and unattractive pharmacological and biopharmaceutical properties. Here, we show that highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) can suppress HD pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. We have validated Sir2 as the in vivo target of selisistat by showing that genetic elimination of Sir2 eradicates the effect of this inhibitor in Drosophila. The specificity of selisistat is shown by its effect on recombinant sirtuins in mammalian cells. Reduction of HD pathology by selisistat in Drosophila, mammalian cells and mouse models of HD suggests that this inhibitor has potential as an effective therapeutic treatment for human disease and may also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for HD. |Animals [MESH] |Carbazoles/*administration & dosage [MESH] |Disease Models, Animal [MESH] |Drosophila Proteins/*antagonists & inhibitors/genetics/metabolism [MESH] |Drosophila melanogaster/drug effects/genetics/metabolism [MESH] |Enzyme Inhibitors/*administration & dosage [MESH] |Female [MESH] |Histone Deacetylases/genetics/metabolism [MESH] |Humans [MESH] |Huntington Disease/*drug therapy/*enzymology/genetics/pathology [MESH] |Male [MESH] |Mice [MESH] |Mice, Inbred C57BL [MESH] |PC12 Cells [MESH] |Rats [MESH] |Rats, Sprague-Dawley [MESH] |Sirtuin 1/*antagonists & inhibitors/genetics/metabolism [MESH]A potent and selective Sirtuin 1 inhibitor alleviates pathology in mul(epmc).pdf DeepDyve Pubget Overpricing