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The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases
Sirtuins are a family of phylogenetically conserved nicotinamide adenine dinucleotide-dependent deacetylases that have a firmly established role in aging. Using a simple Saccharomyces cerevisiae yeast heterochromatic derepression assay, we tested a number of environmental chemicals to address the po...
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Published in: | PLoS genetics 2005-12, Vol.1 (6), p.e77 |
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description | Sirtuins are a family of phylogenetically conserved nicotinamide adenine dinucleotide-dependent deacetylases that have a firmly established role in aging. Using a simple Saccharomyces cerevisiae yeast heterochromatic derepression assay, we tested a number of environmental chemicals to address the possibility that humans are exposed to sirtuin inhibitors. Here we show that dihydrocoumarin (DHC), a compound found in Melilotus officinalis (sweet clover) that is commonly added to food and cosmetics, disrupted heterochromatic silencing and inhibited yeast Sir2p as well as human SIRT1 deacetylase activity. DHC exposure in the human TK6 lymphoblastoid cell line also caused concentration-dependent increases in p53 acetylation and cytotoxicity. Flow cytometric analysis to detect annexin V binding to phosphatidylserine demonstrated that DHC increased apoptosis more than 3-fold over controls. Thus, DHC inhibits both yeast Sir2p and human SIRT1 deacetylases and increases p53 acetylation and apoptosis, a phenotype associated with senescence and aging. These findings demonstrate that humans are potentially exposed to epigenetic toxicants that inhibit sirtuin deacetylases. |
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Using a simple Saccharomyces cerevisiae yeast heterochromatic derepression assay, we tested a number of environmental chemicals to address the possibility that humans are exposed to sirtuin inhibitors. Here we show that dihydrocoumarin (DHC), a compound found in Melilotus officinalis (sweet clover) that is commonly added to food and cosmetics, disrupted heterochromatic silencing and inhibited yeast Sir2p as well as human SIRT1 deacetylase activity. DHC exposure in the human TK6 lymphoblastoid cell line also caused concentration-dependent increases in p53 acetylation and cytotoxicity. Flow cytometric analysis to detect annexin V binding to phosphatidylserine demonstrated that DHC increased apoptosis more than 3-fold over controls. Thus, DHC inhibits both yeast Sir2p and human SIRT1 deacetylases and increases p53 acetylation and apoptosis, a phenotype associated with senescence and aging. These findings demonstrate that humans are potentially exposed to epigenetic toxicants that inhibit sirtuin deacetylases.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.0010077</identifier><identifier>PMID: 16362078</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aging ; Apoptosis ; Cell culture ; Cell Line, Tumor ; Cellular Senescence ; Coumarins - pharmacology ; Cytotoxicity ; Epigenesis, Genetic ; Epigenetics ; Experiments ; Flavoring Agents - pharmacology ; Fungal Proteins - chemistry ; Gene Silencing ; Genetics ; Genetics/Epigenetics ; Histone Deacetylase Inhibitors ; Histone Deacetylases - genetics ; Humans ; In Vitro ; Melilotus officinalis ; Phenotype ; Proteins ; Ribosomal DNA ; Saccharomyces ; Saccharomyces cerevisiae ; Silent Information Regulator Proteins, Saccharomyces cerevisiae - antagonists & inhibitors ; Silent Information Regulator Proteins, Saccharomyces cerevisiae - genetics ; Sirtuin 1 ; Sirtuin 2 ; Sirtuins - antagonists & inhibitors ; Sirtuins - genetics ; Toxicology - Environmental Health ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>PLoS genetics, 2005-12, Vol.1 (6), p.e77</ispartof><rights>2005 Olaharski et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Olaharski AJ, Rine J, Marshall BL, Babiarz J, Zhang L, et al. (2005) The Flavoring Agent Dihydrocoumarin Reverses Epigenetic Silencing and Inhibits Sirtuin Deacetylases. PLoS Genet 1(6): e77. doi:10.1371/journal.pgen.0010077</rights><rights>Copyright: © 2005 Olaharski et al. 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-a3b273a60130916b876a207f15de97bc9db2d8e12bf9cabf009c4d091629a7ea3</citedby><cites>FETCH-LOGICAL-c691t-a3b273a60130916b876a207f15de97bc9db2d8e12bf9cabf009c4d091629a7ea3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1313483020/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1313483020?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16362078$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Dutcher, Susan</contributor><creatorcontrib>Olaharski, Andrew J</creatorcontrib><creatorcontrib>Rine, Jasper</creatorcontrib><creatorcontrib>Marshall, Brett L</creatorcontrib><creatorcontrib>Babiarz, Joshua</creatorcontrib><creatorcontrib>Zhang, Luoping</creatorcontrib><creatorcontrib>Verdin, Eric</creatorcontrib><creatorcontrib>Smith, Martyn T</creatorcontrib><title>The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>Sirtuins are a family of phylogenetically conserved nicotinamide adenine dinucleotide-dependent deacetylases that have a firmly established role in aging. Using a simple Saccharomyces cerevisiae yeast heterochromatic derepression assay, we tested a number of environmental chemicals to address the possibility that humans are exposed to sirtuin inhibitors. Here we show that dihydrocoumarin (DHC), a compound found in Melilotus officinalis (sweet clover) that is commonly added to food and cosmetics, disrupted heterochromatic silencing and inhibited yeast Sir2p as well as human SIRT1 deacetylase activity. DHC exposure in the human TK6 lymphoblastoid cell line also caused concentration-dependent increases in p53 acetylation and cytotoxicity. Flow cytometric analysis to detect annexin V binding to phosphatidylserine demonstrated that DHC increased apoptosis more than 3-fold over controls. Thus, DHC inhibits both yeast Sir2p and human SIRT1 deacetylases and increases p53 acetylation and apoptosis, a phenotype associated with senescence and aging. These findings demonstrate that humans are potentially exposed to epigenetic toxicants that inhibit sirtuin deacetylases.</description><subject>Aging</subject><subject>Apoptosis</subject><subject>Cell culture</subject><subject>Cell Line, Tumor</subject><subject>Cellular Senescence</subject><subject>Coumarins - pharmacology</subject><subject>Cytotoxicity</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Experiments</subject><subject>Flavoring Agents - pharmacology</subject><subject>Fungal Proteins - chemistry</subject><subject>Gene Silencing</subject><subject>Genetics</subject><subject>Genetics/Epigenetics</subject><subject>Histone Deacetylase Inhibitors</subject><subject>Histone Deacetylases - genetics</subject><subject>Humans</subject><subject>In Vitro</subject><subject>Melilotus officinalis</subject><subject>Phenotype</subject><subject>Proteins</subject><subject>Ribosomal DNA</subject><subject>Saccharomyces</subject><subject>Saccharomyces cerevisiae</subject><subject>Silent Information Regulator Proteins, Saccharomyces cerevisiae - antagonists & inhibitors</subject><subject>Silent Information Regulator Proteins, Saccharomyces cerevisiae - genetics</subject><subject>Sirtuin 1</subject><subject>Sirtuin 2</subject><subject>Sirtuins - antagonists & inhibitors</subject><subject>Sirtuins - genetics</subject><subject>Toxicology - Environmental Health</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNptUk2LFDEUbERx19V_INogeJsxH92dzkWQxY-FBS_rObwkLzMZMp0x6R6Yf296p9Vd8ZTwUlWpelRVvaZkTbmgH3ZxSgOE9WGDw5oQSogQT6pL2rZ8JRrSPH1wv6he5LwjhLe9FM-rC9rxjhHRX1bmbou1C3CMyQ-bGorYWFu_PdkUTZz2UMZ1wiOmjLnGgy8AHL2psw84mHvOYGs_bL32Yy7jNE6FYhEMjqcAhfayeuYgZHy1nFfVjy-f766_rW6_f725_nS7Mp2k4wq4ZoJDRygnkna6Fx0Uk462FqXQRlrNbI-UaScNaEeINI2doUyCQOBX1duz7iHErJb9ZEU55U3PCSMFcXNG2Ag7dUi-5DupCF7dD2LaKEglXUBFqXWGmoZgz5oOjW7ASte0WshWdsQVrY_Lb5PeozVlcQnCI9HHL4Pfqk08zn5a1s9m3i8CKf6cMI9q77PBEGDAOBXfsmetaGUBvvsH-P9szRllUsw5oftjhRI1N-Y3S82NUUtjCu3Nwxh_SUtF-C8K6sGa</recordid><startdate>20051201</startdate><enddate>20051201</enddate><creator>Olaharski, Andrew J</creator><creator>Rine, Jasper</creator><creator>Marshall, Brett L</creator><creator>Babiarz, Joshua</creator><creator>Zhang, Luoping</creator><creator>Verdin, Eric</creator><creator>Smith, Martyn T</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7U7</scope><scope>C1K</scope><scope>M7N</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20051201</creationdate><title>The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases</title><author>Olaharski, Andrew J ; Rine, Jasper ; Marshall, Brett L ; Babiarz, Joshua ; Zhang, Luoping ; Verdin, Eric ; Smith, Martyn T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-a3b273a60130916b876a207f15de97bc9db2d8e12bf9cabf009c4d091629a7ea3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Aging</topic><topic>Apoptosis</topic><topic>Cell culture</topic><topic>Cell Line, Tumor</topic><topic>Cellular Senescence</topic><topic>Coumarins - pharmacology</topic><topic>Cytotoxicity</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetics</topic><topic>Experiments</topic><topic>Flavoring Agents - pharmacology</topic><topic>Fungal Proteins - chemistry</topic><topic>Gene Silencing</topic><topic>Genetics</topic><topic>Genetics/Epigenetics</topic><topic>Histone Deacetylase Inhibitors</topic><topic>Histone Deacetylases - genetics</topic><topic>Humans</topic><topic>In Vitro</topic><topic>Melilotus officinalis</topic><topic>Phenotype</topic><topic>Proteins</topic><topic>Ribosomal DNA</topic><topic>Saccharomyces</topic><topic>Saccharomyces cerevisiae</topic><topic>Silent Information Regulator Proteins, Saccharomyces cerevisiae - antagonists & inhibitors</topic><topic>Silent Information Regulator Proteins, Saccharomyces cerevisiae - genetics</topic><topic>Sirtuin 1</topic><topic>Sirtuin 2</topic><topic>Sirtuins - antagonists & inhibitors</topic><topic>Sirtuins - genetics</topic><topic>Toxicology - Environmental Health</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Olaharski, Andrew J</creatorcontrib><creatorcontrib>Rine, Jasper</creatorcontrib><creatorcontrib>Marshall, Brett L</creatorcontrib><creatorcontrib>Babiarz, Joshua</creatorcontrib><creatorcontrib>Zhang, Luoping</creatorcontrib><creatorcontrib>Verdin, Eric</creatorcontrib><creatorcontrib>Smith, Martyn T</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Biological Science Journals</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Olaharski, Andrew J</au><au>Rine, Jasper</au><au>Marshall, Brett L</au><au>Babiarz, Joshua</au><au>Zhang, Luoping</au><au>Verdin, Eric</au><au>Smith, Martyn T</au><au>Dutcher, Susan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2005-12-01</date><risdate>2005</risdate><volume>1</volume><issue>6</issue><spage>e77</spage><pages>e77-</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>Sirtuins are a family of phylogenetically conserved nicotinamide adenine dinucleotide-dependent deacetylases that have a firmly established role in aging. Using a simple Saccharomyces cerevisiae yeast heterochromatic derepression assay, we tested a number of environmental chemicals to address the possibility that humans are exposed to sirtuin inhibitors. Here we show that dihydrocoumarin (DHC), a compound found in Melilotus officinalis (sweet clover) that is commonly added to food and cosmetics, disrupted heterochromatic silencing and inhibited yeast Sir2p as well as human SIRT1 deacetylase activity. DHC exposure in the human TK6 lymphoblastoid cell line also caused concentration-dependent increases in p53 acetylation and cytotoxicity. Flow cytometric analysis to detect annexin V binding to phosphatidylserine demonstrated that DHC increased apoptosis more than 3-fold over controls. Thus, DHC inhibits both yeast Sir2p and human SIRT1 deacetylases and increases p53 acetylation and apoptosis, a phenotype associated with senescence and aging. These findings demonstrate that humans are potentially exposed to epigenetic toxicants that inhibit sirtuin deacetylases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>16362078</pmid><doi>10.1371/journal.pgen.0010077</doi><oa>free_for_read</oa></addata></record> |
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subjects | Aging Apoptosis Cell culture Cell Line, Tumor Cellular Senescence Coumarins - pharmacology Cytotoxicity Epigenesis, Genetic Epigenetics Experiments Flavoring Agents - pharmacology Fungal Proteins - chemistry Gene Silencing Genetics Genetics/Epigenetics Histone Deacetylase Inhibitors Histone Deacetylases - genetics Humans In Vitro Melilotus officinalis Phenotype Proteins Ribosomal DNA Saccharomyces Saccharomyces cerevisiae Silent Information Regulator Proteins, Saccharomyces cerevisiae - antagonists & inhibitors Silent Information Regulator Proteins, Saccharomyces cerevisiae - genetics Sirtuin 1 Sirtuin 2 Sirtuins - antagonists & inhibitors Sirtuins - genetics Toxicology - Environmental Health Tumor Suppressor Protein p53 - metabolism |
title | The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases |
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