Sipjeondaebo-tang Alleviates Oxidative Stress-Mediated Liver Injury through Activation of the CaMKK2-AMPK Signaling Pathway
Sipjeondaebo-tang (SDT) is used frequently as a herbal prescription to treat deficiency syndromes in traditional Korean medicine. We investigated the hepatoprotective effects of SDT against oxidative stress and attempted to clarify the underlying molecular mechanisms. SDT pretreatment reduced arachi...
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| Veröffentlicht in: | Evidence-based complementary and alternative medicine 2018-01, Vol.2018 (2018), p.1-13 |
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| creator | Park, Chung A. Kim, Kwang Joong Cho, Il Je Ku, Sae-Kwang Byun, Sung Hui Lee, Jong Rok Im, Chae Kwang Ko, Hae Li Jung, Eun Hye Kim, Sung Woo Park, Sang Mi Kim, Sang Chan |
| description | Sipjeondaebo-tang (SDT) is used frequently as a herbal prescription to treat deficiency syndromes in traditional Korean medicine. We investigated the hepatoprotective effects of SDT against oxidative stress and attempted to clarify the underlying molecular mechanisms. SDT pretreatment reduced arachidonic acid (AA) plus iron-mediated cytotoxicity in a concentration-dependent manner and prevented changes in apoptosis-related protein expression. In addition, SDT pretreatment significantly reduced glutathione depletion, hydrogen peroxide production, and mitochondrial dysfunction via treatment with AA plus iron. SDT increased the phosphorylation of AMP-activated protein kinase (AMPK) in accordance with the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Experiments using an AMPK chemical inhibitor (Compound C) or CaMKK2 chemical inhibitor (STO-609) suggested that the CaMKK2-AMPK signaling pathway contributes to SDT-mediated protection of mitochondria and cells. Moreover, administration of SDT for 4 consecutive days to mice significantly reduced the alanine aminotransferase and aspartate aminotransferase activities induced by carbon tetrachloride, and the numbers of degenerated hepatocytes, infiltrated inflammatory cells, nitrotyrosine-positive cells, and 4-hydroxynonenal-positive cells in liver tissue. Therefore, SDT protects hepatocytes from oxidative stress via CaMKK2-dependent AMPK activation and has the therapeutic potential to prevent or treat oxidative stress-related liver injury. |
| doi_str_mv | 10.1155/2018/8609285 |
| format | Article |
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We investigated the hepatoprotective effects of SDT against oxidative stress and attempted to clarify the underlying molecular mechanisms. SDT pretreatment reduced arachidonic acid (AA) plus iron-mediated cytotoxicity in a concentration-dependent manner and prevented changes in apoptosis-related protein expression. In addition, SDT pretreatment significantly reduced glutathione depletion, hydrogen peroxide production, and mitochondrial dysfunction via treatment with AA plus iron. SDT increased the phosphorylation of AMP-activated protein kinase (AMPK) in accordance with the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Experiments using an AMPK chemical inhibitor (Compound C) or CaMKK2 chemical inhibitor (STO-609) suggested that the CaMKK2-AMPK signaling pathway contributes to SDT-mediated protection of mitochondria and cells. Moreover, administration of SDT for 4 consecutive days to mice significantly reduced the alanine aminotransferase and aspartate aminotransferase activities induced by carbon tetrachloride, and the numbers of degenerated hepatocytes, infiltrated inflammatory cells, nitrotyrosine-positive cells, and 4-hydroxynonenal-positive cells in liver tissue. Therefore, SDT protects hepatocytes from oxidative stress via CaMKK2-dependent AMPK activation and has the therapeutic potential to prevent or treat oxidative stress-related liver injury.</description><identifier>ISSN: 1741-427X</identifier><identifier>EISSN: 1741-4288</identifier><identifier>DOI: 10.1155/2018/8609285</identifier><identifier>PMID: 30524483</identifier><language>eng</language><publisher>Cairo, Egypt: Hindawi Publishing Corporation</publisher><subject>4-Hydroxynonenal ; Activation ; Alanine ; Alanine transaminase ; AMP ; AMP-activated protein kinase ; Apoptosis ; Arachidonic acid ; Aspartate aminotransferase ; Ca2+/calmodulin-dependent protein kinase ; Calcium ions ; Calcium-binding protein ; Calcium-binding proteins ; Calmodulin ; Carbon tetrachloride ; Cytotoxicity ; Evidence-based medicine ; Glucose ; Glutathione ; Hepatocytes ; Hydrogen peroxide ; Hydrogen reduction ; Inflammation ; Instrument industry ; Iron ; Kinases ; Liver ; Mitochondria ; Molecular modelling ; Nitrotyrosine ; Oxidation ; Oxidative stress ; Phosphorylation ; Pretreatment ; Protein kinases ; Signal transduction</subject><ispartof>Evidence-based complementary and alternative medicine, 2018-01, Vol.2018 (2018), p.1-13</ispartof><rights>Copyright © 2018 Sang Mi Park et al.</rights><rights>COPYRIGHT 2018 John Wiley & Sons, Inc.</rights><rights>Copyright © 2018 Sang Mi Park et al. This is an open access article distributed under the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. https://creativecommons.org/licenses/by/4.0</rights><rights>Copyright © 2018 Sang Mi Park et al. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c499t-618cec54a6489ab0c6a966269dff64fe30821af4fe63c219153131b8f41d2f663</citedby><cites>FETCH-LOGICAL-c499t-618cec54a6489ab0c6a966269dff64fe30821af4fe63c219153131b8f41d2f663</cites><orcidid>0000-0003-3845-6268 ; 0000-0003-3192-839X ; 0000-0001-6295-0608 ; 0000-0003-1269-3804 ; 0000-0003-0515-0764 ; 0000-0003-0988-7763</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247439/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247439/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30524483$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kao, Shao-Hsuan</contributor><contributor>Shao-Hsuan Kao</contributor><creatorcontrib>Park, Chung A.</creatorcontrib><creatorcontrib>Kim, Kwang Joong</creatorcontrib><creatorcontrib>Cho, Il Je</creatorcontrib><creatorcontrib>Ku, Sae-Kwang</creatorcontrib><creatorcontrib>Byun, Sung Hui</creatorcontrib><creatorcontrib>Lee, Jong Rok</creatorcontrib><creatorcontrib>Im, Chae Kwang</creatorcontrib><creatorcontrib>Ko, Hae Li</creatorcontrib><creatorcontrib>Jung, Eun Hye</creatorcontrib><creatorcontrib>Kim, Sung Woo</creatorcontrib><creatorcontrib>Park, Sang Mi</creatorcontrib><creatorcontrib>Kim, Sang Chan</creatorcontrib><title>Sipjeondaebo-tang Alleviates Oxidative Stress-Mediated Liver Injury through Activation of the CaMKK2-AMPK Signaling Pathway</title><title>Evidence-based complementary and alternative medicine</title><addtitle>Evid Based Complement Alternat Med</addtitle><description>Sipjeondaebo-tang (SDT) is used frequently as a herbal prescription to treat deficiency syndromes in traditional Korean medicine. We investigated the hepatoprotective effects of SDT against oxidative stress and attempted to clarify the underlying molecular mechanisms. SDT pretreatment reduced arachidonic acid (AA) plus iron-mediated cytotoxicity in a concentration-dependent manner and prevented changes in apoptosis-related protein expression. In addition, SDT pretreatment significantly reduced glutathione depletion, hydrogen peroxide production, and mitochondrial dysfunction via treatment with AA plus iron. SDT increased the phosphorylation of AMP-activated protein kinase (AMPK) in accordance with the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Experiments using an AMPK chemical inhibitor (Compound C) or CaMKK2 chemical inhibitor (STO-609) suggested that the CaMKK2-AMPK signaling pathway contributes to SDT-mediated protection of mitochondria and cells. Moreover, administration of SDT for 4 consecutive days to mice significantly reduced the alanine aminotransferase and aspartate aminotransferase activities induced by carbon tetrachloride, and the numbers of degenerated hepatocytes, infiltrated inflammatory cells, nitrotyrosine-positive cells, and 4-hydroxynonenal-positive cells in liver tissue. Therefore, SDT protects hepatocytes from oxidative stress via CaMKK2-dependent AMPK activation and has the therapeutic potential to prevent or treat oxidative stress-related liver injury.</description><subject>4-Hydroxynonenal</subject><subject>Activation</subject><subject>Alanine</subject><subject>Alanine transaminase</subject><subject>AMP</subject><subject>AMP-activated protein kinase</subject><subject>Apoptosis</subject><subject>Arachidonic acid</subject><subject>Aspartate aminotransferase</subject><subject>Ca2+/calmodulin-dependent protein kinase</subject><subject>Calcium ions</subject><subject>Calcium-binding protein</subject><subject>Calcium-binding proteins</subject><subject>Calmodulin</subject><subject>Carbon tetrachloride</subject><subject>Cytotoxicity</subject><subject>Evidence-based medicine</subject><subject>Glucose</subject><subject>Glutathione</subject><subject>Hepatocytes</subject><subject>Hydrogen peroxide</subject><subject>Hydrogen reduction</subject><subject>Inflammation</subject><subject>Instrument industry</subject><subject>Iron</subject><subject>Kinases</subject><subject>Liver</subject><subject>Mitochondria</subject><subject>Molecular modelling</subject><subject>Nitrotyrosine</subject><subject>Oxidation</subject><subject>Oxidative stress</subject><subject>Phosphorylation</subject><subject>Pretreatment</subject><subject>Protein kinases</subject><subject>Signal transduction</subject><issn>1741-427X</issn><issn>1741-4288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkUuP0zAUhSMEYh6wY40ssUGCMH7FcTZIUcVj1FYzUkFiZ7nJdeoqjTt20pmKP4-jlg6wYuWrez6d46uTJK8I_kBIll1RTOSVFLigMnuSnJOck5RTKZ-e5vzHWXIRwhpjWuR5_jw5YzijnEt2nvxc2O0aXFdrWLq0112DyraFndU9BHTzYGvd2x2gRe8hhHQO9ajUaBaXHl1368HvUb_ybmhWqKwiG3nXIWfiFtBEz6dTmpbz2yla2KbTrY0Jt7pf3ev9i-SZ0W2Al8f3Mvn--dO3ydd0dvPlelLO0ooXRZ8KIiuoMq4Fl4Ve4kroQggqitoYwQ0wLCnRJk6CVZQUJGOEkaU0nNTUCMEuk48H3-2w3EBdQdd73aqttxvt98ppq_5WOrtSjdspQXnOWREN3h4NvLsbIPRqY0MFbas7cENQNPYgZR6jI_rmH3TtBh_vHimWYcol5o9Uo1tQtjMu5lajqSpF1CNJx9j3B6ryLgQP5vRlgtXYvRq7V8fuI_76zzNP8O-yI_DuAKxs7Pve_qcdRAaMfqRJJkRG2S_qdb_w</recordid><startdate>20180101</startdate><enddate>20180101</enddate><creator>Park, 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Alleviates Oxidative Stress-Mediated Liver Injury through Activation of the CaMKK2-AMPK Signaling Pathway</title><author>Park, Chung A. ; Kim, Kwang Joong ; Cho, Il Je ; Ku, Sae-Kwang ; Byun, Sung Hui ; Lee, Jong Rok ; Im, Chae Kwang ; Ko, Hae Li ; Jung, Eun Hye ; Kim, Sung Woo ; Park, Sang Mi ; Kim, Sang Chan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-618cec54a6489ab0c6a966269dff64fe30821af4fe63c219153131b8f41d2f663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>4-Hydroxynonenal</topic><topic>Activation</topic><topic>Alanine</topic><topic>Alanine transaminase</topic><topic>AMP</topic><topic>AMP-activated protein kinase</topic><topic>Apoptosis</topic><topic>Arachidonic acid</topic><topic>Aspartate aminotransferase</topic><topic>Ca2+/calmodulin-dependent protein kinase</topic><topic>Calcium ions</topic><topic>Calcium-binding protein</topic><topic>Calcium-binding proteins</topic><topic>Calmodulin</topic><topic>Carbon tetrachloride</topic><topic>Cytotoxicity</topic><topic>Evidence-based medicine</topic><topic>Glucose</topic><topic>Glutathione</topic><topic>Hepatocytes</topic><topic>Hydrogen peroxide</topic><topic>Hydrogen reduction</topic><topic>Inflammation</topic><topic>Instrument industry</topic><topic>Iron</topic><topic>Kinases</topic><topic>Liver</topic><topic>Mitochondria</topic><topic>Molecular modelling</topic><topic>Nitrotyrosine</topic><topic>Oxidation</topic><topic>Oxidative stress</topic><topic>Phosphorylation</topic><topic>Pretreatment</topic><topic>Protein kinases</topic><topic>Signal transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Park, Chung A.</creatorcontrib><creatorcontrib>Kim, Kwang Joong</creatorcontrib><creatorcontrib>Cho, Il Je</creatorcontrib><creatorcontrib>Ku, Sae-Kwang</creatorcontrib><creatorcontrib>Byun, Sung 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titles)</collection><jtitle>Evidence-based complementary and alternative medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Park, Chung A.</au><au>Kim, Kwang Joong</au><au>Cho, Il Je</au><au>Ku, Sae-Kwang</au><au>Byun, Sung Hui</au><au>Lee, Jong Rok</au><au>Im, Chae Kwang</au><au>Ko, Hae Li</au><au>Jung, Eun Hye</au><au>Kim, Sung Woo</au><au>Park, Sang Mi</au><au>Kim, Sang Chan</au><au>Kao, Shao-Hsuan</au><au>Shao-Hsuan Kao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sipjeondaebo-tang Alleviates Oxidative Stress-Mediated Liver Injury through Activation of the CaMKK2-AMPK Signaling Pathway</atitle><jtitle>Evidence-based complementary and alternative medicine</jtitle><addtitle>Evid Based Complement Alternat Med</addtitle><date>2018-01-01</date><risdate>2018</risdate><volume>2018</volume><issue>2018</issue><spage>1</spage><epage>13</epage><pages>1-13</pages><issn>1741-427X</issn><eissn>1741-4288</eissn><abstract>Sipjeondaebo-tang (SDT) is used frequently as a herbal prescription to treat deficiency syndromes in traditional Korean medicine. We investigated the hepatoprotective effects of SDT against oxidative stress and attempted to clarify the underlying molecular mechanisms. SDT pretreatment reduced arachidonic acid (AA) plus iron-mediated cytotoxicity in a concentration-dependent manner and prevented changes in apoptosis-related protein expression. In addition, SDT pretreatment significantly reduced glutathione depletion, hydrogen peroxide production, and mitochondrial dysfunction via treatment with AA plus iron. SDT increased the phosphorylation of AMP-activated protein kinase (AMPK) in accordance with the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Experiments using an AMPK chemical inhibitor (Compound C) or CaMKK2 chemical inhibitor (STO-609) suggested that the CaMKK2-AMPK signaling pathway contributes to SDT-mediated protection of mitochondria and cells. Moreover, administration of SDT for 4 consecutive days to mice significantly reduced the alanine aminotransferase and aspartate aminotransferase activities induced by carbon tetrachloride, and the numbers of degenerated hepatocytes, infiltrated inflammatory cells, nitrotyrosine-positive cells, and 4-hydroxynonenal-positive cells in liver tissue. Therefore, SDT protects hepatocytes from oxidative stress via CaMKK2-dependent AMPK activation and has the therapeutic potential to prevent or treat oxidative stress-related liver injury.</abstract><cop>Cairo, Egypt</cop><pub>Hindawi Publishing Corporation</pub><pmid>30524483</pmid><doi>10.1155/2018/8609285</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-3845-6268</orcidid><orcidid>https://orcid.org/0000-0003-3192-839X</orcidid><orcidid>https://orcid.org/0000-0001-6295-0608</orcidid><orcidid>https://orcid.org/0000-0003-1269-3804</orcidid><orcidid>https://orcid.org/0000-0003-0515-0764</orcidid><orcidid>https://orcid.org/0000-0003-0988-7763</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; Wiley Online Library Open Access; PubMed Central; Alma/SFX Local Collection |
| subjects | 4-Hydroxynonenal Activation Alanine Alanine transaminase AMP AMP-activated protein kinase Apoptosis Arachidonic acid Aspartate aminotransferase Ca2+/calmodulin-dependent protein kinase Calcium ions Calcium-binding protein Calcium-binding proteins Calmodulin Carbon tetrachloride Cytotoxicity Evidence-based medicine Glucose Glutathione Hepatocytes Hydrogen peroxide Hydrogen reduction Inflammation Instrument industry Iron Kinases Liver Mitochondria Molecular modelling Nitrotyrosine Oxidation Oxidative stress Phosphorylation Pretreatment Protein kinases Signal transduction |
| title | Sipjeondaebo-tang Alleviates Oxidative Stress-Mediated Liver Injury through Activation of the CaMKK2-AMPK Signaling Pathway |
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