Nrf2‐mediated liver protection by sauchinone, an antioxidant lignan, from acetaminophen toxicity through the PKCδ‐GSK3β pathway
BACKGROUND AND PURPOSE Sauchinone, an antioxidant lignan, protects hepatocytes from iron‐induced toxicity. This study investigated the protective effects of sauchinone against acetaminophen (APAP)‐induced toxicity in the liver and the role of nuclear factor erythroid‐2‐related factor‐2 (Nrf2) in thi...
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| creator | Kay, Hee Yeon Kim, Young Woo Ryu, Da Hye Sung, Sang Hyun Hwang, Se Jin Kim, Sang Geon |
| description | BACKGROUND AND PURPOSE Sauchinone, an antioxidant lignan, protects hepatocytes from iron‐induced toxicity. This study investigated the protective effects of sauchinone against acetaminophen (APAP)‐induced toxicity in the liver and the role of nuclear factor erythroid‐2‐related factor‐2 (Nrf2) in this effect.
EXPERIMENTAL APPROACH Blood biochemistry and histopathology were assessed in mice treated with APAP or APAP + sauchinone. The levels of mRNA and protein were measured using real‐time PCR assays and immunoblottings.
KEY RESULTS Sauchinone ameliorated liver injury caused by a high dose of APAP. This effect was prevented by a deficiency of Nrf2. Sauchinone treatment induced modifier subunit of glutamate‐cysteine ligase, NAD(P)H:quinone oxidoreductase‐1 (NQO1) and heat shock protein 32 in the liver, which was abolished by Nrf2 deficiency. In a hepatocyte model, sauchinone activated Nrf2, as evidenced by the increased nuclear accumulation of Nrf2, the induction of NQO1‐antioxidant response element reporter gene, and glutamate‐cysteine ligase and NQO1 protein induction, which contributed to the restoration of hepatic glutathione content. Consistently, treatment of sauchinone enhanced Nrf2 phosphorylation with a reciprocal decrease in its interaction with Kelch‐like ECH‐associated protein‐1. Intriguingly, sauchinone activated protein kinase C‐δ (PKCδ), which led to Nrf2 phosphorylation. In addition, it increased the inhibitory phosphorylation of glycogen synthase kinase‐3β (GSK3β), derepressing Nrf2 activity, which was supported by the reversal of sauchinone's activation of Nrf2 by an activated mutant of GSK3β. Moreover, phosphorylation of GSK3β by sauchinone depended on PKCδ activation.
CONCLUSION AND IMPLICATIONS Our results demonstrate that sauchinone protects the liver from APAP‐induced toxicity by activating Nrf2, and this effect is mediated by PKCδ activation, which induces inhibitory phosphorylation of GSK3β. |
| doi_str_mv | 10.1111/j.1476-5381.2010.01095.x |
| format | Article |
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EXPERIMENTAL APPROACH Blood biochemistry and histopathology were assessed in mice treated with APAP or APAP + sauchinone. The levels of mRNA and protein were measured using real‐time PCR assays and immunoblottings.
KEY RESULTS Sauchinone ameliorated liver injury caused by a high dose of APAP. This effect was prevented by a deficiency of Nrf2. Sauchinone treatment induced modifier subunit of glutamate‐cysteine ligase, NAD(P)H:quinone oxidoreductase‐1 (NQO1) and heat shock protein 32 in the liver, which was abolished by Nrf2 deficiency. In a hepatocyte model, sauchinone activated Nrf2, as evidenced by the increased nuclear accumulation of Nrf2, the induction of NQO1‐antioxidant response element reporter gene, and glutamate‐cysteine ligase and NQO1 protein induction, which contributed to the restoration of hepatic glutathione content. Consistently, treatment of sauchinone enhanced Nrf2 phosphorylation with a reciprocal decrease in its interaction with Kelch‐like ECH‐associated protein‐1. Intriguingly, sauchinone activated protein kinase C‐δ (PKCδ), which led to Nrf2 phosphorylation. In addition, it increased the inhibitory phosphorylation of glycogen synthase kinase‐3β (GSK3β), derepressing Nrf2 activity, which was supported by the reversal of sauchinone's activation of Nrf2 by an activated mutant of GSK3β. Moreover, phosphorylation of GSK3β by sauchinone depended on PKCδ activation.
CONCLUSION AND IMPLICATIONS Our results demonstrate that sauchinone protects the liver from APAP‐induced toxicity by activating Nrf2, and this effect is mediated by PKCδ activation, which induces inhibitory phosphorylation of GSK3β.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/j.1476-5381.2010.01095.x</identifier><identifier>PMID: 21039417</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>acetaminophen ; Acetaminophen - toxicity ; Analgesics, Non-Narcotic - toxicity ; Animals ; Antioxidants - chemistry ; Antioxidants - metabolism ; Antioxidants - pharmacology ; Benzopyrans - chemistry ; Benzopyrans - metabolism ; Benzopyrans - pharmacology ; Biological and medical sciences ; Dioxoles - chemistry ; Dioxoles - metabolism ; Dioxoles - pharmacology ; Glutathione - analysis ; Glycogen Synthase Kinase 3 - genetics ; Glycogen Synthase Kinase 3 - metabolism ; Glycogen Synthase Kinase 3 beta ; GSK3β ; Hep G2 Cells ; Humans ; Lignans - chemistry ; Lignans - metabolism ; Lignans - pharmacology ; Liver - drug effects ; Liver - injuries ; Liver - metabolism ; Liver - pathology ; Major Histocompatibility Complex - genetics ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-E2-Related Factor 2 - physiology ; Nrf2 ; Pharmacology. Drug treatments ; Phytotherapy ; PKCδ ; Plant Preparations - chemistry ; Plant Preparations - metabolism ; Plant Preparations - pharmacology ; Protective Agents - chemistry ; Protective Agents - metabolism ; Protective Agents - pharmacology ; Protein Kinase C-delta - genetics ; Protein Kinase C-delta - metabolism ; Proteins - genetics ; Proteins - metabolism ; Research Papers ; sauchinone ; Saururaceae ; Signal Transduction - drug effects ; Signal Transduction - physiology</subject><ispartof>British journal of pharmacology, 2011-08, Vol.163 (8), p.1653-1665</ispartof><rights>2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society</rights><rights>2015 INIST-CNRS</rights><rights>2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.</rights><rights>British Journal of Pharmacology © 2011 The British Pharmacological Society 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5035-50c33cfd109c63a6099ba3cae5c15f7b2c3794f93a70019e67ec957957b59aa63</citedby><cites>FETCH-LOGICAL-c5035-50c33cfd109c63a6099ba3cae5c15f7b2c3794f93a70019e67ec957957b59aa63</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/PMC3166693/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166693/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24401229$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21039417$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kay, Hee Yeon</creatorcontrib><creatorcontrib>Kim, Young Woo</creatorcontrib><creatorcontrib>Ryu, Da Hye</creatorcontrib><creatorcontrib>Sung, Sang Hyun</creatorcontrib><creatorcontrib>Hwang, Se Jin</creatorcontrib><creatorcontrib>Kim, Sang Geon</creatorcontrib><title>Nrf2‐mediated liver protection by sauchinone, an antioxidant lignan, from acetaminophen toxicity through the PKCδ‐GSK3β pathway</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>BACKGROUND AND PURPOSE Sauchinone, an antioxidant lignan, protects hepatocytes from iron‐induced toxicity. This study investigated the protective effects of sauchinone against acetaminophen (APAP)‐induced toxicity in the liver and the role of nuclear factor erythroid‐2‐related factor‐2 (Nrf2) in this effect.
EXPERIMENTAL APPROACH Blood biochemistry and histopathology were assessed in mice treated with APAP or APAP + sauchinone. The levels of mRNA and protein were measured using real‐time PCR assays and immunoblottings.
KEY RESULTS Sauchinone ameliorated liver injury caused by a high dose of APAP. This effect was prevented by a deficiency of Nrf2. Sauchinone treatment induced modifier subunit of glutamate‐cysteine ligase, NAD(P)H:quinone oxidoreductase‐1 (NQO1) and heat shock protein 32 in the liver, which was abolished by Nrf2 deficiency. In a hepatocyte model, sauchinone activated Nrf2, as evidenced by the increased nuclear accumulation of Nrf2, the induction of NQO1‐antioxidant response element reporter gene, and glutamate‐cysteine ligase and NQO1 protein induction, which contributed to the restoration of hepatic glutathione content. Consistently, treatment of sauchinone enhanced Nrf2 phosphorylation with a reciprocal decrease in its interaction with Kelch‐like ECH‐associated protein‐1. Intriguingly, sauchinone activated protein kinase C‐δ (PKCδ), which led to Nrf2 phosphorylation. In addition, it increased the inhibitory phosphorylation of glycogen synthase kinase‐3β (GSK3β), derepressing Nrf2 activity, which was supported by the reversal of sauchinone's activation of Nrf2 by an activated mutant of GSK3β. Moreover, phosphorylation of GSK3β by sauchinone depended on PKCδ activation.
CONCLUSION AND IMPLICATIONS Our results demonstrate that sauchinone protects the liver from APAP‐induced toxicity by activating Nrf2, and this effect is mediated by PKCδ activation, which induces inhibitory phosphorylation of GSK3β.</description><subject>acetaminophen</subject><subject>Acetaminophen - toxicity</subject><subject>Analgesics, Non-Narcotic - toxicity</subject><subject>Animals</subject><subject>Antioxidants - chemistry</subject><subject>Antioxidants - metabolism</subject><subject>Antioxidants - pharmacology</subject><subject>Benzopyrans - chemistry</subject><subject>Benzopyrans - metabolism</subject><subject>Benzopyrans - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Dioxoles - chemistry</subject><subject>Dioxoles - metabolism</subject><subject>Dioxoles - pharmacology</subject><subject>Glutathione - analysis</subject><subject>Glycogen Synthase Kinase 3 - genetics</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>GSK3β</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Lignans - chemistry</subject><subject>Lignans - metabolism</subject><subject>Lignans - pharmacology</subject><subject>Liver - drug effects</subject><subject>Liver - injuries</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Major Histocompatibility Complex - genetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>NF-E2-Related Factor 2 - physiology</subject><subject>Nrf2</subject><subject>Pharmacology. Drug treatments</subject><subject>Phytotherapy</subject><subject>PKCδ</subject><subject>Plant Preparations - chemistry</subject><subject>Plant Preparations - metabolism</subject><subject>Plant Preparations - pharmacology</subject><subject>Protective Agents - chemistry</subject><subject>Protective Agents - metabolism</subject><subject>Protective Agents - pharmacology</subject><subject>Protein Kinase C-delta - genetics</subject><subject>Protein Kinase C-delta - metabolism</subject><subject>Proteins - genetics</subject><subject>Proteins - metabolism</subject><subject>Research Papers</subject><subject>sauchinone</subject><subject>Saururaceae</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcFu1DAQhi0EokvhFZAv3JqtHcfx-gASXUGLWrWVgLM18Tobr7JO5GTbzY0Ld54F8Rx9iD4JE7YscMOyNZb_b2Y8-gmhnE05ruPVlGcqT6SY8WnK8BWPltPtIzLZC4_JhDGmEs5nswPyrOtWjKGo5FNykHImdMbVhHy9jGV6_-Xb2i089G5Ba3_jIm1j0zvb-ybQYqAdbGzlQxPcEYWAG4WtX2BEfBkgHNEyNmsK1vWwRrCtXKA9Mtb3A-2r2GyWFUZHr8_ndz-w3-nHc3H3nbbQV7cwPCdPSqg79-IhHpLP7999mp8lF1enH-ZvLxIrmZCJZFYIWy5wWJsLyJnWBQgLTlouS1WkViidlVqAwlm1y5WzWirchdQAuTgkb3Z1202BE1sX-gi1aaNfQxxMA978qwRfmWVzYwTP81wLLDDbFbCx6broyn0uZ2a0xqzM6IAZHTCjNeaXNWaLqS__7r1P_O0FAq8eAOgs1GWEYH33h8syxtNUI_d6x9362g3__QFzcn023sRPQFCwjw</recordid><startdate>201108</startdate><enddate>201108</enddate><creator>Kay, Hee Yeon</creator><creator>Kim, Young Woo</creator><creator>Ryu, Da Hye</creator><creator>Sung, Sang Hyun</creator><creator>Hwang, Se Jin</creator><creator>Kim, Sang Geon</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing Group</general><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>5PM</scope></search><sort><creationdate>201108</creationdate><title>Nrf2‐mediated liver protection by sauchinone, an antioxidant lignan, from acetaminophen toxicity through the PKCδ‐GSK3β pathway</title><author>Kay, Hee Yeon ; Kim, Young Woo ; Ryu, Da Hye ; Sung, Sang Hyun ; Hwang, Se Jin ; Kim, Sang Geon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5035-50c33cfd109c63a6099ba3cae5c15f7b2c3794f93a70019e67ec957957b59aa63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>acetaminophen</topic><topic>Acetaminophen - toxicity</topic><topic>Analgesics, Non-Narcotic - toxicity</topic><topic>Animals</topic><topic>Antioxidants - chemistry</topic><topic>Antioxidants - metabolism</topic><topic>Antioxidants - pharmacology</topic><topic>Benzopyrans - chemistry</topic><topic>Benzopyrans - metabolism</topic><topic>Benzopyrans - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Dioxoles - chemistry</topic><topic>Dioxoles - metabolism</topic><topic>Dioxoles - pharmacology</topic><topic>Glutathione - analysis</topic><topic>Glycogen Synthase Kinase 3 - genetics</topic><topic>Glycogen Synthase Kinase 3 - metabolism</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>GSK3β</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Lignans - chemistry</topic><topic>Lignans - metabolism</topic><topic>Lignans - pharmacology</topic><topic>Liver - drug effects</topic><topic>Liver - injuries</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Major Histocompatibility Complex - genetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>NF-E2-Related Factor 2 - physiology</topic><topic>Nrf2</topic><topic>Pharmacology. Drug treatments</topic><topic>Phytotherapy</topic><topic>PKCδ</topic><topic>Plant Preparations - chemistry</topic><topic>Plant Preparations - metabolism</topic><topic>Plant Preparations - pharmacology</topic><topic>Protective Agents - chemistry</topic><topic>Protective Agents - metabolism</topic><topic>Protective Agents - pharmacology</topic><topic>Protein Kinase C-delta - genetics</topic><topic>Protein Kinase C-delta - metabolism</topic><topic>Proteins - genetics</topic><topic>Proteins - metabolism</topic><topic>Research Papers</topic><topic>sauchinone</topic><topic>Saururaceae</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kay, Hee Yeon</creatorcontrib><creatorcontrib>Kim, Young Woo</creatorcontrib><creatorcontrib>Ryu, Da Hye</creatorcontrib><creatorcontrib>Sung, Sang Hyun</creatorcontrib><creatorcontrib>Hwang, Se Jin</creatorcontrib><creatorcontrib>Kim, Sang Geon</creatorcontrib><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>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kay, Hee Yeon</au><au>Kim, Young Woo</au><au>Ryu, Da Hye</au><au>Sung, Sang Hyun</au><au>Hwang, Se Jin</au><au>Kim, Sang Geon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nrf2‐mediated liver protection by sauchinone, an antioxidant lignan, from acetaminophen toxicity through the PKCδ‐GSK3β pathway</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2011-08</date><risdate>2011</risdate><volume>163</volume><issue>8</issue><spage>1653</spage><epage>1665</epage><pages>1653-1665</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><coden>BJPCBM</coden><abstract>BACKGROUND AND PURPOSE Sauchinone, an antioxidant lignan, protects hepatocytes from iron‐induced toxicity. This study investigated the protective effects of sauchinone against acetaminophen (APAP)‐induced toxicity in the liver and the role of nuclear factor erythroid‐2‐related factor‐2 (Nrf2) in this effect.
EXPERIMENTAL APPROACH Blood biochemistry and histopathology were assessed in mice treated with APAP or APAP + sauchinone. The levels of mRNA and protein were measured using real‐time PCR assays and immunoblottings.
KEY RESULTS Sauchinone ameliorated liver injury caused by a high dose of APAP. This effect was prevented by a deficiency of Nrf2. Sauchinone treatment induced modifier subunit of glutamate‐cysteine ligase, NAD(P)H:quinone oxidoreductase‐1 (NQO1) and heat shock protein 32 in the liver, which was abolished by Nrf2 deficiency. In a hepatocyte model, sauchinone activated Nrf2, as evidenced by the increased nuclear accumulation of Nrf2, the induction of NQO1‐antioxidant response element reporter gene, and glutamate‐cysteine ligase and NQO1 protein induction, which contributed to the restoration of hepatic glutathione content. Consistently, treatment of sauchinone enhanced Nrf2 phosphorylation with a reciprocal decrease in its interaction with Kelch‐like ECH‐associated protein‐1. Intriguingly, sauchinone activated protein kinase C‐δ (PKCδ), which led to Nrf2 phosphorylation. In addition, it increased the inhibitory phosphorylation of glycogen synthase kinase‐3β (GSK3β), derepressing Nrf2 activity, which was supported by the reversal of sauchinone's activation of Nrf2 by an activated mutant of GSK3β. Moreover, phosphorylation of GSK3β by sauchinone depended on PKCδ activation.
CONCLUSION AND IMPLICATIONS Our results demonstrate that sauchinone protects the liver from APAP‐induced toxicity by activating Nrf2, and this effect is mediated by PKCδ activation, which induces inhibitory phosphorylation of GSK3β.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>21039417</pmid><doi>10.1111/j.1476-5381.2010.01095.x</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | acetaminophen Acetaminophen - toxicity Analgesics, Non-Narcotic - toxicity Animals Antioxidants - chemistry Antioxidants - metabolism Antioxidants - pharmacology Benzopyrans - chemistry Benzopyrans - metabolism Benzopyrans - pharmacology Biological and medical sciences Dioxoles - chemistry Dioxoles - metabolism Dioxoles - pharmacology Glutathione - analysis Glycogen Synthase Kinase 3 - genetics Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta GSK3β Hep G2 Cells Humans Lignans - chemistry Lignans - metabolism Lignans - pharmacology Liver - drug effects Liver - injuries Liver - metabolism Liver - pathology Major Histocompatibility Complex - genetics Male Medical sciences Mice Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2 - physiology Nrf2 Pharmacology. Drug treatments Phytotherapy PKCδ Plant Preparations - chemistry Plant Preparations - metabolism Plant Preparations - pharmacology Protective Agents - chemistry Protective Agents - metabolism Protective Agents - pharmacology Protein Kinase C-delta - genetics Protein Kinase C-delta - metabolism Proteins - genetics Proteins - metabolism Research Papers sauchinone Saururaceae Signal Transduction - drug effects Signal Transduction - physiology |
| title | Nrf2‐mediated liver protection by sauchinone, an antioxidant lignan, from acetaminophen toxicity through the PKCδ‐GSK3β pathway |
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