Branched-Chain Amino Acid Supplementation Reduces Oxidative Stress and Prolongs Survival in Rats with Advanced Liver Cirrhosis
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{"title"=>"Branched-Chain Amino Acid Supplementation Reduces Oxidative Stress and Prolongs Survival in Rats with Advanced Liver Cirrhosis", "type"=>"journal", "authors"=>[{"first_name"=>"Motoh", "last_name"=>"Iwasa", "scopus_author_id"=>"7103255771"}, {"first_name"=>"Yoshinao", "last_name"=>"Kobayashi", "scopus_author_id"=>"35240303600"}, {"first_name"=>"Rumi", "last_name"=>"Mifuji-Moroka", "scopus_author_id"=>"48861657800"}, {"first_name"=>"Nagisa", "last_name"=>"Hara", "scopus_author_id"=>"15022482500"}, {"first_name"=>"Hirohide", "last_name"=>"Miyachi", "scopus_author_id"=>"26030631500"}, {"first_name"=>"Ryosuke", "last_name"=>"Sugimoto", "scopus_author_id"=>"14052853300"}, {"first_name"=>"Hideaki", "last_name"=>"Tanaka", "scopus_author_id"=>"55624472097"}, {"first_name"=>"Naoki", "last_name"=>"Fujita", "scopus_author_id"=>"7402023156"}, {"first_name"=>"Esteban C.", "last_name"=>"Gabazza", "scopus_author_id"=>"7006628179"}, {"first_name"=>"Yoshiyuki", "last_name"=>"Takei", "scopus_author_id"=>"7202470579"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84880810939", "sgr"=>"84880810939", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0070309", "pmid"=>"23936183", "pui"=>"369439058"}, "id"=>"fa11dbbf-b744-3bb3-a9e4-150bacf68f81", "abstract"=>"Long-term supplementation with branched-chain amino acids (BCAA) is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (P<0.05). The prolonged survival due to BCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver.", "link"=>"http://www.mendeley.com/research/branchedchain-amino-acid-supplementation-reduces-oxidative-stress-prolongs-survival-rats-advanced-li-1", "reader_count"=>24, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>3, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>3, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>2, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>10, "Medicine and Dentistry"=>10, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>10}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}}, "reader_count_by_country"=>{"United States"=>1, "Japan"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1131776"], "description"=>"<p>On the 5<sup>th</sup> week, histological examination of the liver was performed in three rats, and fibrosis consistent with liver cirrhosis was found in all rats (Fig. 1-A, magnification×40). Liver histology on the 21<sup>st</sup> week showed liver cirrhosis in control rats (Fig. 1-B, magnification×40). Liver histology on the 21<sup>st</sup> week showed liver cirrhosis in BCAA-treated rats (Fig. 1-C, magnification×40). Azan-positive area in the sample was identified as green color using the Lumina Vision digital analyzing system. The picture in (Fig. 1-D) was derived from (Fig. 1-C). The green and total areas were digitally measured. CCl<sub>4</sub>, carbon tetrachloride.</p>", "links"=>[], "tags"=>["Anatomy and physiology", "Physiological processes", "Energy metabolism", "Biochemistry", "metabolism", "Gastroenterology and hepatology", "Liver diseases", "cirrhosis", "nutrition", "fibrosis"], "article_id"=>755661, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Motoh Iwasa", "Yoshinao Kobayashi", "Rumi Mifuji-Moroka", "Nagisa Hara", "Hirohide Miyachi", "Ryosuke Sugimoto", "Hideaki Tanaka", "Naoki Fujita", "Esteban C. Gabazza", "Yoshiyuki Takei"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0070309.g001", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Liver_fibrosis_in_CCl_4_treated_rats_/755661", "title"=>"Liver fibrosis in CCl<sub>4</sub>-treated rats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 03:17:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1131784"], "description"=>"<p>Cells were cultured with or without 2.4 mM of DEM for 2 h. Western blotting of p-c Jun, p-JNK and non-phosphorylated FoxO1 in the nuclear fraction, and p-FoxO1, PEPCK, G6P and β-actin in the cytoplasmic fraction of cultured cells (Fig. 8-A). Protein expression level of the p-c Jun was enhanced by DEM (n = 4), but was repressed by BCAA supplementation (n = 4) (Fig. 8-B). Protein expression of p-JNK was enhanced by DEM (n = 4), but it was repressed by BCAA supplementation (n = 4) (Fig. 8-C). Protein expression of FoxO1 was enhanced by DEM (n = 4), but it was repressed by BCAA supplementation (n = 4) (Fig. 8-D). The rate of FoxO1 to p-FoxO1 was elevated by DEM (n = 4), but it was repressed by BCAA supplementation (n = 4) (Fig. 8-E). Protein expression of PEPCK was enhanced by DEM (n = 4), but it was repressed by BCAA supplementation (n = 4) (Fig. 8-F). Protein expression of G6P was enhanced by DEM (n = 4), but it was repressed by BCAA supplementation (n = 4) (Fig. 8-G). DEM, diethylmaleate; BCAA, branched-chain amino acids; p-c Jun, phosphorylated c-Jun, p-JNK, phosphorylated c-Jun N-terminal kinase; FoxO1, forkhead box O1; p-FoxO1, phosphorylated forkhead box O1; PEPCK, phosphoenolpyruvate carboxykinase; G6P, glucose 6-phosphatase.</p>", "links"=>[], "tags"=>["Anatomy and physiology", "Physiological processes", "Energy metabolism", "Biochemistry", "metabolism", "Gastroenterology and hepatology", "Liver diseases", "cirrhosis", "nutrition", "bcaa", "jnk-foxo1", "pathway-mediated", "gluconeogenesis", "cultured"], "article_id"=>755669, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Motoh Iwasa", "Yoshinao Kobayashi", "Rumi Mifuji-Moroka", "Nagisa Hara", "Hirohide Miyachi", "Ryosuke Sugimoto", "Hideaki Tanaka", "Naoki Fujita", "Esteban C. Gabazza", "Yoshiyuki Takei"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0070309.g008", "stats"=>{"downloads"=>5, "page_views"=>103, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_BCAA_on_JNK_FoxO1_pathway_mediated_gluconeogenesis_in_cultured_cells_/755669", "title"=>"Effect of BCAA on JNK-FoxO1 pathway-mediated gluconeogenesis in cultured cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 03:17:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1131783"], "description"=>"<p>The gene expression of <i>Jnk</i> was measured by real-time PCR and the relative quantities of <i>Jnk</i> mRNA in the liver were normalized to <i>Gapdh</i> mRNA (Fig. 7-A). The expression of <i>FoxO1</i> was measured by real-time PCR and the relative quantities of <i>FoxO1</i> mRNA in the liver were normalized to <i>Gapdh</i> mRNA (Fig. 7-B). The expression of <i>Pepck</i> was measured by real-time PCR and the relative quantities of <i>Pepck</i> mRNA in the liver were normalized to <i>Gapdh</i> mRNA (Fig. 7-C). The expression of <i>G6p</i> was measured by real-time PCR and the relative quantities of <i>G6p</i> mRNA in the liver were normalized to <i>Gapdh</i> mRNA (Fig. 7-D). The expressions of <i>Jnk</i> (Fig. 7-A), <i>FoxO1</i> (Fig. 7-B), <i>Pepck</i> (Fig. 7-C) and <i>G6p</i> (Fig. 7-D) were downregulated in the livers of the BCAA group (closed columns, n = 6) compared to the control group (open columns, n = 4). Jnk, c-Jun N-terminal kinase; PCR, polymerase chain reaction; FoxO1, forkhead box O1; Pepck, phosphoenolpyruvate carboxykinase; G6p, glucose 6-phosphatase; BCAA, branched-chain amino acids.</p>", "links"=>[], "tags"=>["Anatomy and physiology", "Physiological processes", "Energy metabolism", "Biochemistry", "metabolism", "Gastroenterology and hepatology", "Liver diseases", "cirrhosis", "nutrition", "gluconeogenesis", "foxo1-dependent"], "article_id"=>755668, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Motoh Iwasa", "Yoshinao Kobayashi", "Rumi Mifuji-Moroka", "Nagisa Hara", "Hirohide Miyachi", "Ryosuke Sugimoto", "Hideaki Tanaka", "Naoki Fujita", "Esteban C. Gabazza", "Yoshiyuki Takei"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0070309.g007", "stats"=>{"downloads"=>1, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hepatic_gluconeogenesis_through_FoxO1_dependent_pathway_/755668", "title"=>"Hepatic gluconeogenesis through FoxO1-dependent pathway.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 03:17:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1131780"], "description"=>"<p>A strong intracellular 4-Hne adduct immunostaining (grade 3) is detected in the liver of rats not supplemented with BCAA (Fig. 4-A; Left, magnification×25; Right, magnification×400). A mild intracellular 4-Hne adduct immunostaining (grade 1) is detected in the liver of rats supplemented with BCAA (Fig. 4-B; Left, magnification×25; Right, magnification×400). 4-Hne index is decreased in the BCAA supplementation group (closed columns, n = 6) compared to the control group (open columns, n = 4) (Fig. 4-C). Hepatic 8-OHdG concentration is decreased in the BCAA supplementation group (closed columns, n = 6) compared to the control group (open columns, n = 4) (Fig. 4-D). 4-Hne, 4-hydroxynonenal; BCAA, branched-chain amino acids; 8-OHdG, 8-hydroxy-2′-deoxyguanosine.</p>", "links"=>[], "tags"=>["Anatomy and physiology", "Physiological processes", "Energy metabolism", "Biochemistry", "metabolism", "Gastroenterology and hepatology", "Liver diseases", "cirrhosis", "nutrition", "4-hne", "adducts", "rats"], "article_id"=>755665, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Motoh Iwasa", "Yoshinao Kobayashi", "Rumi Mifuji-Moroka", "Nagisa Hara", "Hirohide Miyachi", "Ryosuke Sugimoto", "Hideaki Tanaka", "Naoki Fujita", "Esteban C. Gabazza", "Yoshiyuki Takei"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0070309.g004", "stats"=>{"downloads"=>9, "page_views"=>82, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immunohistochemistry_of_4_Hne_adducts_in_rats_with_advanced_liver_cirrhosis_/755665", "title"=>"Immunohistochemistry of 4-Hne adducts in rats with advanced liver cirrhosis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 03:17:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1131778"], "description"=>"<p>Kaplan-Meier survival curves of rats supplemented or not with BCAA with p values calculated using the log rank test. A significant improvement in survival was observed in BCAA supplemented rats (Fig. 2-A, P<0.05). Body weight of rats supplemented or not with BCAA. There was no significant change in the body weight of rats supplemented or not with BCAA (Fig. 2-B). Food intake of rats supplemented or not with BCAA. Daily food intake was less in the BCAA group than in the control group (Fig. 2-C). BCAA, branched-chain amino acids.</p>", "links"=>[], "tags"=>["Anatomy and physiology", "Physiological processes", "Energy metabolism", "Biochemistry", "metabolism", "Gastroenterology and hepatology", "Liver diseases", "cirrhosis", "nutrition", "supplementation", "prolongs", "rats"], "article_id"=>755663, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Motoh Iwasa", "Yoshinao Kobayashi", "Rumi Mifuji-Moroka", "Nagisa Hara", "Hirohide Miyachi", "Ryosuke Sugimoto", "Hideaki Tanaka", "Naoki Fujita", "Esteban C. Gabazza", "Yoshiyuki Takei"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0070309.g002", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BCAA_supplementation_prolongs_survival_of_rats_with_advanced_liver_cirrhosis_/755663", "title"=>"BCAA supplementation prolongs survival of rats with advanced liver cirrhosis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 03:17:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1131779"], "description"=>"<p>Serum aminotransferase activities and total bilirubin levels tended to be lower in rats treated with BCAA (n = 7) than in those without BCAA (n = 5) on weeks 17 (Fig. 3-A). Serum albumin also tended to be higher in BCAA group (n = 7) on weeks 17 (Fig. 3-A). The serum insulin concentration in the BCAA treatment group (n = 6) was lower than in the controls (n = 4) on weeks 21. However, the serum glucose concentration was not differs between groups (Fig. 3-B). BCAA, branched-chain amino acids.</p>", "links"=>[], "tags"=>["Anatomy and physiology", "Physiological processes", "Energy metabolism", "Biochemistry", "metabolism", "Gastroenterology and hepatology", "Liver diseases", "cirrhosis", "nutrition", "animals", "weeks", "17"], "article_id"=>755664, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Motoh Iwasa", "Yoshinao Kobayashi", "Rumi Mifuji-Moroka", "Nagisa Hara", "Hirohide Miyachi", "Ryosuke Sugimoto", "Hideaki Tanaka", "Naoki Fujita", "Esteban C. Gabazza", "Yoshiyuki Takei"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0070309.g003", "stats"=>{"downloads"=>2, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Biochemical_data_of_animals_on_weeks_17_or_21_/755664", "title"=>"Biochemical data of animals on weeks 17 or 21.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 03:17:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1131782"], "description"=>"<p>Hepatic iron concentration was measured by atomic absorption spectrometry in rats. Rats fed BCAA mixture (closed columns, n = 6) had lower hepatic iron contents than those fed saline (open columns, n = 4) (P<0.05) on weeks 21 (Fig. 6-A). The gene expression levels of <i>hepcidin</i> were measured by real-time PCR and the relative quantities of <i>hepcidin</i> mRNA in the liver were normalized to <i>Gapdh</i> mRNA. Serum hepcidin was measured by surface-enhanced laser desorption/ionization time of flight mass spectrometry (Fig. 6-B). The gene expression levels of <i>Tfr1</i> were measured by real-time PCR and the relative quantities of <i>Tfr1</i> mRNA in the liver were normalized to <i>Gapdh</i> mRNA. Western blotting of Tfr1 in the liver and the relative quantity of Tfr1 were normalized against beta-actin (Fig. 6-C). The gene expression of <i>Fp1</i> was measured by real-time PCR and the relative quantity of <i>Fp1</i> mRNA in the liver were normalized against <i>Gapdh</i> mRNA. Western blotting of Fp1 in the liver and the relative quantity of Fp1 were normalized against beta-actin (Fig. 6-D). The levels of hepcidin (Fig. 6-B) and Fp1 (Fig. 6-D) were downregulated and those of Tfr1 (Fig. 6-C) were upregulated in the livers of the BCAA group (closed columns, n = 6) on weeks 21. BCAA, branched-chain amino acids; PCR, polymerase chain reaction; Tfr1, transferrin receptor 1; Fp1, ferroportin 1.</p>", "links"=>[], "tags"=>["Anatomy and physiology", "Physiological processes", "Energy metabolism", "Biochemistry", "metabolism", "Gastroenterology and hepatology", "Liver diseases", "cirrhosis", "nutrition", "accumulation", "transporters"], "article_id"=>755667, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Motoh Iwasa", "Yoshinao Kobayashi", "Rumi Mifuji-Moroka", "Nagisa Hara", "Hirohide Miyachi", "Ryosuke Sugimoto", "Hideaki Tanaka", "Naoki Fujita", "Esteban C. Gabazza", "Yoshiyuki Takei"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0070309.g006", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hepatic_iron_accumulation_and_expression_of_iron_transporters_in_liver_/755667", "title"=>"Hepatic iron accumulation and expression of iron transporters in liver.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 03:17:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1131781"], "description"=>"<p>Copper/zinc Sod (Sod1, Fig. 5-A) and manganese Sod (Sod2, Fig. 5-B) protein levels were increased in the BCAA supplementation group (closed columns, n = 6) compared to the control group (open columns, n = 4). Western blotting of Sod2 protein in mitochondrial fraction is shown in Fig. 5-C. BCAA, branched-chain amino acids; ROS, reactive oxygen species; Sod, superoxide dismutase.</p>", "links"=>[], "tags"=>["Anatomy and physiology", "Physiological processes", "Energy metabolism", "Biochemistry", "metabolism", "Gastroenterology and hepatology", "Liver diseases", "cirrhosis", "nutrition", "upregulates", "ros"], "article_id"=>755666, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Motoh Iwasa", "Yoshinao Kobayashi", "Rumi Mifuji-Moroka", "Nagisa Hara", "Hirohide Miyachi", "Ryosuke Sugimoto", "Hideaki Tanaka", "Naoki Fujita", "Esteban C. Gabazza", "Yoshiyuki Takei"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0070309.g005", "stats"=>{"downloads"=>1, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BCAA_upregulates_ROS_defense_system_in_the_liver_/755666", "title"=>"BCAA upregulates ROS defense system in the liver.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 03:17:19"}

PMC Usage Stats | Further Information

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Relative Metric

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