Plasma and liver proteomic analysis of 3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one-induced hepatotoxicity in Wistar rats
3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one (Z24), a synthetic anti-angiogenic compound, inhibits the growth and metastasis of certain tumors. Previous works have shown that Z24 induces hepatotoxicity in rodents. We examined the hepatotoxic mechanism of Z24 at the...
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| Veröffentlicht in: | Proteomics (Weinheim) 2010-08, Vol.10 (16), p.2927-2941 |
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| creator | Wang, Ying Yang, Baohua Wu, Chunqi Zheng, Zhibing Yuan, Ye Hu, ZhongHui Ma, HuaZhi Li, Song Liao, Mingyang Wang, Quanjun |
| description | 3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one (Z24), a synthetic anti-angiogenic compound, inhibits the growth and metastasis of certain tumors. Previous works have shown that Z24 induces hepatotoxicity in rodents. We examined the hepatotoxic mechanism of Z24 at the protein level and looked for potential biomarkers. We used 2-DE and MALDI-TOF/TOF MS to analyze alternatively expressed proteins in rat liver and plasma after Z24 administration. We also examined apoptosis in rat liver and measured levels of intramitochondrial ROS and NAD(P)H redox in liver cells. We found that 22 nonredundant proteins in the liver and 11 in the plasma were differentially expressed. These proteins were involved in several important metabolic pathways, including carbohydrate, lipid, amino acid, and energy metabolism, biotransformation, apoptosis, etc. Apoptosis in rat liver was confirmed with the terminal deoxynucleotidyl transferase dUTP-nick end labeling assay. In mitochondria, Z24 increased the ROS and decreased the NAD(P)H levels. Thus, inhibition of carbohydrate aerobic oxidation, fatty acid β-oxidation, and oxidative phosphorylation is a potential mechanism of Z24-induced hepatotoxicity, resulting in mitochondrial dysfunction and apoptosis-mediated cell death. In addition, fetub protein and argininosuccinate synthase in plasma may be potential biomarkers of Z24-induced hepatotoxicity. |
| doi_str_mv | 10.1002/pmic.200900699 |
| format | Article |
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Previous works have shown that Z24 induces hepatotoxicity in rodents. We examined the hepatotoxic mechanism of Z24 at the protein level and looked for potential biomarkers. We used 2-DE and MALDI-TOF/TOF MS to analyze alternatively expressed proteins in rat liver and plasma after Z24 administration. We also examined apoptosis in rat liver and measured levels of intramitochondrial ROS and NAD(P)H redox in liver cells. We found that 22 nonredundant proteins in the liver and 11 in the plasma were differentially expressed. These proteins were involved in several important metabolic pathways, including carbohydrate, lipid, amino acid, and energy metabolism, biotransformation, apoptosis, etc. Apoptosis in rat liver was confirmed with the terminal deoxynucleotidyl transferase dUTP-nick end labeling assay. In mitochondria, Z24 increased the ROS and decreased the NAD(P)H levels. Thus, inhibition of carbohydrate aerobic oxidation, fatty acid β-oxidation, and oxidative phosphorylation is a potential mechanism of Z24-induced hepatotoxicity, resulting in mitochondrial dysfunction and apoptosis-mediated cell death. In addition, fetub protein and argininosuccinate synthase in plasma may be potential biomarkers of Z24-induced hepatotoxicity.</description><identifier>ISSN: 1615-9853</identifier><identifier>ISSN: 1615-9861</identifier><identifier>EISSN: 1615-9861</identifier><identifier>DOI: 10.1002/pmic.200900699</identifier><identifier>PMID: 20544730</identifier><language>eng</language><publisher>Weinheim: Wiley-VCH Verlag</publisher><subject>Amino Acids - metabolism ; Analytical, structural and metabolic biochemistry ; Animal proteomics ; Animals ; Apoptosis ; Biological and medical sciences ; Biomarkers ; Blood Proteins - analysis ; Blood Proteins - metabolism ; Chemical and Drug Induced Liver Injury - metabolism ; Dose-Response Relationship, Drug ; Electrophoresis, Gel, Two-Dimensional ; Female ; Fundamental and applied biological sciences. Psychology ; Hepatotoxicity ; Histocytochemistry ; In Situ Nick-End Labeling ; Liver - cytology ; Liver - metabolism ; Mass Spectrometry ; Mesylates - toxicity ; Miscellaneous ; NADP - metabolism ; Proteins ; Proteome - drug effects ; Proteomics - methods ; Pyrroles - toxicity ; Rats ; Rats, Wistar ; Reactive Oxygen Species - metabolism ; Z24</subject><ispartof>Proteomics (Weinheim), 2010-08, Vol.10 (16), p.2927-2941</ispartof><rights>Copyright © 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4689-abe975aca7a32afaee9586e85eb82b275fe0d8e885469b7dc7b60d074439a51a3</citedby><cites>FETCH-LOGICAL-c4689-abe975aca7a32afaee9586e85eb82b275fe0d8e885469b7dc7b60d074439a51a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fpmic.200900699$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fpmic.200900699$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23119366$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20544730$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Ying</creatorcontrib><creatorcontrib>Yang, Baohua</creatorcontrib><creatorcontrib>Wu, Chunqi</creatorcontrib><creatorcontrib>Zheng, Zhibing</creatorcontrib><creatorcontrib>Yuan, Ye</creatorcontrib><creatorcontrib>Hu, ZhongHui</creatorcontrib><creatorcontrib>Ma, HuaZhi</creatorcontrib><creatorcontrib>Li, Song</creatorcontrib><creatorcontrib>Liao, Mingyang</creatorcontrib><creatorcontrib>Wang, Quanjun</creatorcontrib><title>Plasma and liver proteomic analysis of 3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one-induced hepatotoxicity in Wistar rats</title><title>Proteomics (Weinheim)</title><addtitle>Proteomics</addtitle><description>3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one (Z24), a synthetic anti-angiogenic compound, inhibits the growth and metastasis of certain tumors. Previous works have shown that Z24 induces hepatotoxicity in rodents. We examined the hepatotoxic mechanism of Z24 at the protein level and looked for potential biomarkers. We used 2-DE and MALDI-TOF/TOF MS to analyze alternatively expressed proteins in rat liver and plasma after Z24 administration. We also examined apoptosis in rat liver and measured levels of intramitochondrial ROS and NAD(P)H redox in liver cells. We found that 22 nonredundant proteins in the liver and 11 in the plasma were differentially expressed. These proteins were involved in several important metabolic pathways, including carbohydrate, lipid, amino acid, and energy metabolism, biotransformation, apoptosis, etc. Apoptosis in rat liver was confirmed with the terminal deoxynucleotidyl transferase dUTP-nick end labeling assay. In mitochondria, Z24 increased the ROS and decreased the NAD(P)H levels. Thus, inhibition of carbohydrate aerobic oxidation, fatty acid β-oxidation, and oxidative phosphorylation is a potential mechanism of Z24-induced hepatotoxicity, resulting in mitochondrial dysfunction and apoptosis-mediated cell death. In addition, fetub protein and argininosuccinate synthase in plasma may be potential biomarkers of Z24-induced hepatotoxicity.</description><subject>Amino Acids - metabolism</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animal proteomics</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Biomarkers</subject><subject>Blood Proteins - analysis</subject><subject>Blood Proteins - metabolism</subject><subject>Chemical and Drug Induced Liver Injury - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Electrophoresis, Gel, Two-Dimensional</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Hepatotoxicity</subject><subject>Histocytochemistry</subject><subject>In Situ Nick-End Labeling</subject><subject>Liver - cytology</subject><subject>Liver - metabolism</subject><subject>Mass Spectrometry</subject><subject>Mesylates - toxicity</subject><subject>Miscellaneous</subject><subject>NADP - metabolism</subject><subject>Proteins</subject><subject>Proteome - drug effects</subject><subject>Proteomics - methods</subject><subject>Pyrroles - toxicity</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Z24</subject><issn>1615-9853</issn><issn>1615-9861</issn><issn>1615-9861</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9v1DAQxSMEoqVw5Qi5IFoJFzuOY_uIttCtVKASVK2KkDVxJtTF-YOdheaz8GXJkmXhxskjz--9GfslyWNGDxml2cu-cfYwo1RTWmh9J9llBRNEq4Ld3daC7yQPYryhlEml5f1kJ6MizyWnu8nPMw-xgRTaKvXuO4a0D92A3WQ73YEfo4tpV6f8inDyaZ8tST-G0HmSkdEfkAaH69G7Clv8TBjZZ6R3PQZXuXb0c_OAsBecZEvi2uq3rmtxXa8sVuk19jB0Q3frrBvG1LXphYsDhDTAEB8m92rwER9tzr3k_M3rj4slOX1_fLJ4dUpsXihNoEQtBViQwDOoAVELVaASWKqszKSokVYKlRJ5oUtZWVkWtKIyz7kGwYDvJc9n3-np31YYB9O4aNF7aLFbRaMUp3lOJZ_Iw5m0oYsxYG364BoIo2HUrPMw6zzMNo9J8GRjvSobrLb4nwAm4NkGgGjB1wFa6-JfjjOmeVFMnJ65H87j-J-x5uztyeLfJcisnb4Wb7daCF9NIbkU5uLdscmzq6PLy-XCHE3805mvoTPwJUz7nH_IKOOUKcUko_wXG3a9DA</recordid><startdate>20100801</startdate><enddate>20100801</enddate><creator>Wang, Ying</creator><creator>Yang, Baohua</creator><creator>Wu, Chunqi</creator><creator>Zheng, Zhibing</creator><creator>Yuan, Ye</creator><creator>Hu, ZhongHui</creator><creator>Ma, HuaZhi</creator><creator>Li, Song</creator><creator>Liao, Mingyang</creator><creator>Wang, Quanjun</creator><general>Wiley-VCH Verlag</general><general>WILEY-VCH Verlag</general><general>WILEY‐VCH Verlag</general><general>Wiley-VCH</general><scope>FBQ</scope><scope>BSCLL</scope><scope>IQODW</scope><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20100801</creationdate><title>Plasma and liver proteomic analysis of 3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one-induced hepatotoxicity in Wistar rats</title><author>Wang, Ying ; Yang, Baohua ; Wu, Chunqi ; Zheng, Zhibing ; Yuan, Ye ; Hu, ZhongHui ; Ma, HuaZhi ; Li, Song ; Liao, Mingyang ; Wang, Quanjun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4689-abe975aca7a32afaee9586e85eb82b275fe0d8e885469b7dc7b60d074439a51a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Amino Acids - metabolism</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Animal proteomics</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Biomarkers</topic><topic>Blood Proteins - analysis</topic><topic>Blood Proteins - metabolism</topic><topic>Chemical and Drug Induced Liver Injury - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Electrophoresis, Gel, Two-Dimensional</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Hepatotoxicity</topic><topic>Histocytochemistry</topic><topic>In Situ Nick-End Labeling</topic><topic>Liver - cytology</topic><topic>Liver - metabolism</topic><topic>Mass Spectrometry</topic><topic>Mesylates - toxicity</topic><topic>Miscellaneous</topic><topic>NADP - metabolism</topic><topic>Proteins</topic><topic>Proteome - drug effects</topic><topic>Proteomics - methods</topic><topic>Pyrroles - toxicity</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Z24</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Ying</creatorcontrib><creatorcontrib>Yang, Baohua</creatorcontrib><creatorcontrib>Wu, Chunqi</creatorcontrib><creatorcontrib>Zheng, Zhibing</creatorcontrib><creatorcontrib>Yuan, Ye</creatorcontrib><creatorcontrib>Hu, ZhongHui</creatorcontrib><creatorcontrib>Ma, HuaZhi</creatorcontrib><creatorcontrib>Li, Song</creatorcontrib><creatorcontrib>Liao, Mingyang</creatorcontrib><creatorcontrib>Wang, Quanjun</creatorcontrib><collection>AGRIS</collection><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Proteomics (Weinheim)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Ying</au><au>Yang, Baohua</au><au>Wu, Chunqi</au><au>Zheng, Zhibing</au><au>Yuan, Ye</au><au>Hu, ZhongHui</au><au>Ma, HuaZhi</au><au>Li, Song</au><au>Liao, Mingyang</au><au>Wang, Quanjun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Plasma and liver proteomic analysis of 3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one-induced hepatotoxicity in Wistar rats</atitle><jtitle>Proteomics (Weinheim)</jtitle><addtitle>Proteomics</addtitle><date>2010-08-01</date><risdate>2010</risdate><volume>10</volume><issue>16</issue><spage>2927</spage><epage>2941</epage><pages>2927-2941</pages><issn>1615-9853</issn><issn>1615-9861</issn><eissn>1615-9861</eissn><abstract>3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one (Z24), a synthetic anti-angiogenic compound, inhibits the growth and metastasis of certain tumors. Previous works have shown that Z24 induces hepatotoxicity in rodents. We examined the hepatotoxic mechanism of Z24 at the protein level and looked for potential biomarkers. We used 2-DE and MALDI-TOF/TOF MS to analyze alternatively expressed proteins in rat liver and plasma after Z24 administration. We also examined apoptosis in rat liver and measured levels of intramitochondrial ROS and NAD(P)H redox in liver cells. We found that 22 nonredundant proteins in the liver and 11 in the plasma were differentially expressed. These proteins were involved in several important metabolic pathways, including carbohydrate, lipid, amino acid, and energy metabolism, biotransformation, apoptosis, etc. Apoptosis in rat liver was confirmed with the terminal deoxynucleotidyl transferase dUTP-nick end labeling assay. In mitochondria, Z24 increased the ROS and decreased the NAD(P)H levels. Thus, inhibition of carbohydrate aerobic oxidation, fatty acid β-oxidation, and oxidative phosphorylation is a potential mechanism of Z24-induced hepatotoxicity, resulting in mitochondrial dysfunction and apoptosis-mediated cell death. In addition, fetub protein and argininosuccinate synthase in plasma may be potential biomarkers of Z24-induced hepatotoxicity.</abstract><cop>Weinheim</cop><pub>Wiley-VCH Verlag</pub><pmid>20544730</pmid><doi>10.1002/pmic.200900699</doi><tpages>15</tpages></addata></record> |
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| subjects | Amino Acids - metabolism Analytical, structural and metabolic biochemistry Animal proteomics Animals Apoptosis Biological and medical sciences Biomarkers Blood Proteins - analysis Blood Proteins - metabolism Chemical and Drug Induced Liver Injury - metabolism Dose-Response Relationship, Drug Electrophoresis, Gel, Two-Dimensional Female Fundamental and applied biological sciences. Psychology Hepatotoxicity Histocytochemistry In Situ Nick-End Labeling Liver - cytology Liver - metabolism Mass Spectrometry Mesylates - toxicity Miscellaneous NADP - metabolism Proteins Proteome - drug effects Proteomics - methods Pyrroles - toxicity Rats Rats, Wistar Reactive Oxygen Species - metabolism Z24 |
| title | Plasma and liver proteomic analysis of 3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one-induced hepatotoxicity in Wistar rats |
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