Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats
Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpen...
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| Veröffentlicht in: | PloS one 2012-04, Vol.7 (4), p.e34200 |
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| creator | Singh, Brijesh Kumar Tripathi, Madhulika Chaudhari, Bhushan P Pandey, Pramod K Kakkar, Poonam |
| description | Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P |
| doi_str_mv | 10.1371/journal.pone.0034200 |
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In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P<0.001), increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT) followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c). It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P<0.05). A combination of camphene and geraniol (CG; 1:1), when pre-administered in rats (10 mg/kg BW), accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(P)H and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0034200</identifier><identifier>PMID: 22509279</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>8-Hydroxyguanine ; Analgesics ; Animals ; Antioxidants ; Antioxidants (Nutrients) ; Antioxidants - metabolism ; Apoptosis ; Apoptosis Regulatory Proteins - secretion ; Apoptosis-inducing factor ; Arthritis ; Bilirubin ; Biochemistry ; Biocompatibility ; Biological Products - pharmacology ; Biology ; Biomarkers ; Camphene ; Caspase ; Caspase 3 - metabolism ; Caspase 9 - metabolism ; Caspase-3 ; Caspase-9 ; Cell Death - drug effects ; Chemistry ; Clinical medicine ; Copper ; Cytochrome ; Cytochrome c ; Cytoprotection - drug effects ; Damage prevention ; Deoxyribonucleic acid ; Depolarization ; DNA ; DNA Damage ; DNA glycosylase ; DNA-formamidopyrimidine glycosylase ; Drug dosages ; Electron Transport - drug effects ; Endonuclease ; Enzymatic activity ; Enzymes ; Free radicals ; Gene expression ; Hepatitis ; Hepatotoxicity ; Histochemistry ; Histopathology ; Homeostasis ; Homeostasis - drug effects ; Inflammation ; Laboratories ; Lipid Metabolism - drug effects ; Liver - cytology ; Liver - drug effects ; Liver diseases ; Macromolecules ; Male ; Males ; Manganese ; Medicine ; Membrane permeability ; Membrane Potential, Mitochondrial - drug effects ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondria - pathology ; Mitochondria - secretion ; Molecular modelling ; NAD ; Nonsteroidal anti-inflammatory drugs ; Nucleotides - metabolism ; Oxidants - metabolism ; Oxidation resistance ; Oxidative stress ; Oxidative Stress - drug effects ; Oxidizing agents ; Permeability ; Permeability - drug effects ; Proteins ; Proteolysis - drug effects ; Rats ; Rats, Sprague-Dawley ; RNA ; Rodents ; Sulfonamides - toxicity ; Superoxides ; Terpenes ; Terpenes - pharmacology ; Toxicity ; Toxicology ; Transcription, Genetic - drug effects ; Zinc</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e34200</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Singh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Singh et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-ff6b557ecd9c4c4a525558e1f598ff55f62ab6db2bd2bafd17c44f6ad98a3ca83</citedby><cites>FETCH-LOGICAL-c758t-ff6b557ecd9c4c4a525558e1f598ff55f62ab6db2bd2bafd17c44f6ad98a3ca83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317927/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317927/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22509279$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Chan, Sherine Swee Lin</contributor><creatorcontrib>Singh, Brijesh Kumar</creatorcontrib><creatorcontrib>Tripathi, Madhulika</creatorcontrib><creatorcontrib>Chaudhari, Bhushan P</creatorcontrib><creatorcontrib>Pandey, Pramod K</creatorcontrib><creatorcontrib>Kakkar, Poonam</creatorcontrib><title>Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P<0.001), increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT) followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c). It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P<0.05). A combination of camphene and geraniol (CG; 1:1), when pre-administered in rats (10 mg/kg BW), accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(P)H and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity.</description><subject>8-Hydroxyguanine</subject><subject>Analgesics</subject><subject>Animals</subject><subject>Antioxidants</subject><subject>Antioxidants (Nutrients)</subject><subject>Antioxidants - metabolism</subject><subject>Apoptosis</subject><subject>Apoptosis Regulatory Proteins - secretion</subject><subject>Apoptosis-inducing factor</subject><subject>Arthritis</subject><subject>Bilirubin</subject><subject>Biochemistry</subject><subject>Biocompatibility</subject><subject>Biological Products - pharmacology</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Camphene</subject><subject>Caspase</subject><subject>Caspase 3 - metabolism</subject><subject>Caspase 9 - metabolism</subject><subject>Caspase-3</subject><subject>Caspase-9</subject><subject>Cell Death - drug effects</subject><subject>Chemistry</subject><subject>Clinical medicine</subject><subject>Copper</subject><subject>Cytochrome</subject><subject>Cytochrome c</subject><subject>Cytoprotection - drug effects</subject><subject>Damage prevention</subject><subject>Deoxyribonucleic acid</subject><subject>Depolarization</subject><subject>DNA</subject><subject>DNA Damage</subject><subject>DNA glycosylase</subject><subject>DNA-formamidopyrimidine glycosylase</subject><subject>Drug dosages</subject><subject>Electron Transport - drug effects</subject><subject>Endonuclease</subject><subject>Enzymatic activity</subject><subject>Enzymes</subject><subject>Free radicals</subject><subject>Gene expression</subject><subject>Hepatitis</subject><subject>Hepatotoxicity</subject><subject>Histochemistry</subject><subject>Histopathology</subject><subject>Homeostasis</subject><subject>Homeostasis - drug effects</subject><subject>Inflammation</subject><subject>Laboratories</subject><subject>Lipid Metabolism - drug effects</subject><subject>Liver - cytology</subject><subject>Liver - drug effects</subject><subject>Liver diseases</subject><subject>Macromolecules</subject><subject>Male</subject><subject>Males</subject><subject>Manganese</subject><subject>Medicine</subject><subject>Membrane permeability</subject><subject>Membrane Potential, Mitochondrial - drug effects</subject><subject>Mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Mitochondria - secretion</subject><subject>Molecular modelling</subject><subject>NAD</subject><subject>Nonsteroidal anti-inflammatory drugs</subject><subject>Nucleotides - metabolism</subject><subject>Oxidants - metabolism</subject><subject>Oxidation resistance</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Oxidizing agents</subject><subject>Permeability</subject><subject>Permeability - drug effects</subject><subject>Proteins</subject><subject>Proteolysis - drug effects</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>RNA</subject><subject>Rodents</subject><subject>Sulfonamides - toxicity</subject><subject>Superoxides</subject><subject>Terpenes</subject><subject>Terpenes - pharmacology</subject><subject>Toxicity</subject><subject>Toxicology</subject><subject>Transcription, Genetic - drug effects</subject><subject>Zinc</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk2trFDEUhgdRbK3-A9GAIAjummQmc_kilOKlUCx4-xrOJCe7KbPJNMmU7q_wL5u109IFBcmHhJPnvEnenFMUzxldsrJh7y78FBwMy9E7XFJaVpzSB8Uh60q-qDktH95bHxRPYrygVJRtXT8uDjgXtONNd1j8-gJpCjCQhGFEh5GMAa_QJbKxyau1dzrYvK230UxOJevdW-KvrYZkr5DEFDBGAk6TgANCROINgdGPySersphPaF0kegrWrYizG4zTYDUu1jhChrKWsmlLrCMBUnxaPDIwRHw2z0fFj48fvp98Xpydfzo9OT5bqEa0aWFM3QvRoNKdqlQFggshWmRGdK0xQpiaQ1_rnvea92A0a1RVmRp010KpoC2Pipc3uuPgo5y9jJKVVcW6RvA6E6c3hPZwIcdgNxC20oOVfwI-rCSE_MYBpQFjaM2o6jitWNsA6_uu51g3vKQ10qz1fj5t6jeoVfY3e74nur_j7Fqu_JUsS9bkj8oCr2aB4C8njOkfV56pFeRbWWd8FlMbG5U8rpqGVV3biEwt_0LloXFjVa4mY3N8L-HNXkJmEl6nFUwxytNvX_-fPf-5z76-x64RhrSOfph2RRb3weoGVMHHGNDcOceo3DXDrRty1wxyboac9uK-63dJt9Vf_gbbbQpT</recordid><startdate>20120403</startdate><enddate>20120403</enddate><creator>Singh, Brijesh Kumar</creator><creator>Tripathi, Madhulika</creator><creator>Chaudhari, Bhushan P</creator><creator>Pandey, Pramod K</creator><creator>Kakkar, Poonam</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</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>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120403</creationdate><title>Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats</title><author>Singh, Brijesh Kumar ; Tripathi, Madhulika ; Chaudhari, Bhushan P ; Pandey, Pramod K ; Kakkar, Poonam</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-ff6b557ecd9c4c4a525558e1f598ff55f62ab6db2bd2bafd17c44f6ad98a3ca83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>8-Hydroxyguanine</topic><topic>Analgesics</topic><topic>Animals</topic><topic>Antioxidants</topic><topic>Antioxidants (Nutrients)</topic><topic>Antioxidants - metabolism</topic><topic>Apoptosis</topic><topic>Apoptosis Regulatory Proteins - secretion</topic><topic>Apoptosis-inducing factor</topic><topic>Arthritis</topic><topic>Bilirubin</topic><topic>Biochemistry</topic><topic>Biocompatibility</topic><topic>Biological Products - pharmacology</topic><topic>Biology</topic><topic>Biomarkers</topic><topic>Camphene</topic><topic>Caspase</topic><topic>Caspase 3 - metabolism</topic><topic>Caspase 9 - metabolism</topic><topic>Caspase-3</topic><topic>Caspase-9</topic><topic>Cell Death - drug effects</topic><topic>Chemistry</topic><topic>Clinical medicine</topic><topic>Copper</topic><topic>Cytochrome</topic><topic>Cytochrome c</topic><topic>Cytoprotection - drug effects</topic><topic>Damage prevention</topic><topic>Deoxyribonucleic acid</topic><topic>Depolarization</topic><topic>DNA</topic><topic>DNA Damage</topic><topic>DNA glycosylase</topic><topic>DNA-formamidopyrimidine glycosylase</topic><topic>Drug dosages</topic><topic>Electron Transport - drug effects</topic><topic>Endonuclease</topic><topic>Enzymatic activity</topic><topic>Enzymes</topic><topic>Free radicals</topic><topic>Gene expression</topic><topic>Hepatitis</topic><topic>Hepatotoxicity</topic><topic>Histochemistry</topic><topic>Histopathology</topic><topic>Homeostasis</topic><topic>Homeostasis - 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drug effects</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>RNA</topic><topic>Rodents</topic><topic>Sulfonamides - toxicity</topic><topic>Superoxides</topic><topic>Terpenes</topic><topic>Terpenes - pharmacology</topic><topic>Toxicity</topic><topic>Toxicology</topic><topic>Transcription, Genetic - drug effects</topic><topic>Zinc</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Brijesh Kumar</creatorcontrib><creatorcontrib>Tripathi, Madhulika</creatorcontrib><creatorcontrib>Chaudhari, Bhushan P</creatorcontrib><creatorcontrib>Pandey, Pramod K</creatorcontrib><creatorcontrib>Kakkar, Poonam</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</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>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</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>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Singh, Brijesh Kumar</au><au>Tripathi, Madhulika</au><au>Chaudhari, Bhushan P</au><au>Pandey, Pramod K</au><au>Kakkar, Poonam</au><au>Chan, Sherine Swee Lin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-04-03</date><risdate>2012</risdate><volume>7</volume><issue>4</issue><spage>e34200</spage><pages>e34200-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P<0.001), increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT) followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c). It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P<0.05). A combination of camphene and geraniol (CG; 1:1), when pre-administered in rats (10 mg/kg BW), accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(P)H and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22509279</pmid><doi>10.1371/journal.pone.0034200</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-04, Vol.7 (4), p.e34200 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1344197526 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 8-Hydroxyguanine Analgesics Animals Antioxidants Antioxidants (Nutrients) Antioxidants - metabolism Apoptosis Apoptosis Regulatory Proteins - secretion Apoptosis-inducing factor Arthritis Bilirubin Biochemistry Biocompatibility Biological Products - pharmacology Biology Biomarkers Camphene Caspase Caspase 3 - metabolism Caspase 9 - metabolism Caspase-3 Caspase-9 Cell Death - drug effects Chemistry Clinical medicine Copper Cytochrome Cytochrome c Cytoprotection - drug effects Damage prevention Deoxyribonucleic acid Depolarization DNA DNA Damage DNA glycosylase DNA-formamidopyrimidine glycosylase Drug dosages Electron Transport - drug effects Endonuclease Enzymatic activity Enzymes Free radicals Gene expression Hepatitis Hepatotoxicity Histochemistry Histopathology Homeostasis Homeostasis - drug effects Inflammation Laboratories Lipid Metabolism - drug effects Liver - cytology Liver - drug effects Liver diseases Macromolecules Male Males Manganese Medicine Membrane permeability Membrane Potential, Mitochondrial - drug effects Mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitochondria - pathology Mitochondria - secretion Molecular modelling NAD Nonsteroidal anti-inflammatory drugs Nucleotides - metabolism Oxidants - metabolism Oxidation resistance Oxidative stress Oxidative Stress - drug effects Oxidizing agents Permeability Permeability - drug effects Proteins Proteolysis - drug effects Rats Rats, Sprague-Dawley RNA Rodents Sulfonamides - toxicity Superoxides Terpenes Terpenes - pharmacology Toxicity Toxicology Transcription, Genetic - drug effects Zinc |
| title | Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats |
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