The 4′-Hydroxyl Group of Resveratrol Is Functionally Important for Direct Activation of PPARα
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{"title"=>"The 4′-hydroxyl group of resveratrol is functionally important for direct activation of PPARα", "type"=>"journal", "authors"=>[{"first_name"=>"Yoshie", "last_name"=>"Takizawa", "scopus_author_id"=>"54797555800"}, {"first_name"=>"Rieko", "last_name"=>"Nakata", "scopus_author_id"=>"7007015396"}, {"first_name"=>"Kiyoshi", "last_name"=>"Fukuhara", "scopus_author_id"=>"56411715300"}, {"first_name"=>"Hiroshi", "last_name"=>"Yamashita", "scopus_author_id"=>"55813091100"}, {"first_name"=>"Hideo", "last_name"=>"Kubodera", "scopus_author_id"=>"6603221094"}, {"first_name"=>"Hiroyasu", "last_name"=>"Inoue", "scopus_author_id"=>"7404987685"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"603282101", "pmid"=>"25798826", "doi"=>"10.1371/journal.pone.0120865", "sgr"=>"84925799245", "scopus"=>"2-s2.0-84925799245"}, "id"=>"98753cde-7580-3d75-8020-8bd99af2e946", "abstract"=>"Long-term moderate consumption of red wine is associated with a reduced risk of developing lifestyle-related diseases such as cardiovascular disease and cancer. Therefore, resveratrol, a constituent of grapes and various other plants, has attracted substantial interest. This study focused on one molecular target of resveratrol, the peroxisome proliferator activated receptor α (PPARα). Our previous study in mice showed that resveratrol-mediated protection of the brain against stroke requires activation of PPARα; however, the molecular mechanisms involved in this process remain unknown. Here, we evaluated the chemical basis of the resveratrol-mediated activation of PPARα by performing a docking mode simulation and examining the structure-activity relationships of various polyphenols. The results of experiments using the crystal structure of the PPARα ligand-binding domain and an analysis of the activation of PPARα by a resveratrol analog 4-phenylazophenol (4-PAP) in vivo indicate that the 4'-hydroxyl group of resveratrol is critical for the direct activation of PPARα. Activation of PPARα by 5 μM resveratrol was enhanced by rolipram, an inhibitor of phosphodiesterase (PDE) and forskolin, an activator of adenylate cyclase. We also found that resveratrol has a higher PDE inhibitory activity (IC50 = 19 μM) than resveratrol analogs trans-4-hydroxystilbene and 4-PAP (IC50 = 27-28 μM), both of which has only 4'-hydroxyl group, indicating that this 4'-hydroxyl group of resveratrol is not sufficient for the inhibition of PDE. This result is consistent with that 10 μM resveratrol has a higher agonistic activity of PPARα than these analogs, suggesting that there is a feedforward activation loop of PPARα by resveratrol, which may be involved in the long-term effects of resveratrol in vivo.", "link"=>"http://www.mendeley.com/research/4hydroxyl-group-resveratrol-functionally-important-direct-activation-ppar%CE%B1", "reader_count"=>12, "reader_count_by_academic_status"=>{"Researcher"=>3, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Student > Master"=>2, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>3, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Student > Master"=>2, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>3, "Medicine and Dentistry"=>1, "Physics and Astronomy"=>1, "Chemistry"=>3}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>3}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}}, "reader_count_by_country"=>{"Japan"=>1, "Brazil"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1982004"], "description"=>"<p>(A) The chemical structures of resveratrol and its related compounds containing a 4′-hydroxyl group (shown in red). (B) The activation of PPARα by exposure of BAECs transiently transfected with PPRE-luc, GS-hPPARα, and pSV-β-gal to the compounds (5, 10 μM) shown in (A). Data were statistically evaluated using the unpaired <i>t</i>-test. ** <i>p</i> < 0.01, ***<i>p</i> < 0.001 compared with cells treated with 5 μM resveratrol. †††<i>p</i> < 0.001 compared with cells treated with 10 μM resveratrol. <sup>###</sup><i>p</i> < 0.001 compared with cells treated with 4-PAP. (C) The chemical structures of the flavonoids studied. (D) The activation of PPARα by exposure of BAECs transiently transfected with PPRE-luc, GS-hPPARα, and pSV-β-gal to 5 μM of resveratrol or to 5 μM of the flavonoids shown in (C). Data were statistically evaluated using the unpaired <i>t</i>-test. *<i>p</i> < 0.05, ***<i>p</i> < 0.001 compared with cells treated with flavone. (B) and (D) were presented as the relative luciferase activities normalized to those of the β-galactosidase standard, and represent the mean ± SD of three independent wells of cells. Similar results were obtained by two additional experiments.</p>", "links"=>[], "tags"=>["pap", "PPAR α. Activation", "pde", "5 μ M resveratrol", "docking mode simulation", "feedforward activation loop", "IC 50", "PPAR α"], "article_id"=>1350640, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Yoshie Takizawa", "Rieko Nakata", "Kiyoshi Fukuhara", "Hiroshi Yamashita", "Hideo Kubodera", "Hiroyasu Inoue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120865.g001", "stats"=>{"downloads"=>3, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_4_hydroxyl_group_of_resveratrol_is_required_for_the_activation_of_PPAR_in_vitro_/1350640", "title"=>"The 4′-hydroxyl group of resveratrol is required for the activation of PPARα <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-23 04:42:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1982014"], "description"=>"<p>These diagrams present our hypothesis about short- and long-term effects of resveratrol, as shown in the text.</p>", "links"=>[], "tags"=>["pap", "PPAR α. Activation", "pde", "5 μ M resveratrol", "docking mode simulation", "feedforward activation loop", "IC 50", "PPAR α"], "article_id"=>1350650, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Yoshie Takizawa", "Rieko Nakata", "Kiyoshi Fukuhara", "Hiroshi Yamashita", "Hideo Kubodera", "Hiroyasu Inoue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120865.g005", "stats"=>{"downloads"=>4, "page_views"=>159, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Possible_relationship_among_resveratrol_PPAR_945_and_PDE_/1350650", "title"=>"Possible relationship among resveratrol, PPARα and PDE.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-23 04:42:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1982007"], "description"=>"<p>(A) The four docking modes of resveratrol predicted using the GOLD 3.0 docking program [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120865#pone.0120865.ref024\" target=\"_blank\">24</a>] with protein co-ordination data from the PPARα-GW409544 complex structure (PDB ID: 1K7L) and a standard docking protocol. (B) Superimposition of docking mode II of resveratrol (orange) on the structure of PPARα bound to GW409544, a potent PPARα agonist (green). Only the amino acids located near to GW409544 are displayed. The hydrogen bonds of Tyr314 and Tyr464 are shown as dashed green lines. (C) Binding free energies (∆∆Gbind (kcal/mol)) of the indicated PPARα amino acid residues, calculated by alanine scanning using data for the four predicted docking modes. (D) Activation of wild-type (WT) PPARα and its mutants by 5, 50 μM resveratrol or Wy-14643. BAECs were transiently transfected with PPRE-luc, wild-type or mutant GS-hPPARα, and pSV-β-gal. The data are presented as relative luciferase activities normalized to those of the β-galactosidase standard and as 1 for cells treated with DMSO (control), and represent the mean ± SD of three independent wells of cells. Similar results were obtained by two additional experiments. The data were calculated the relative luciferase activity in cells transfected with wild-type PPARα.</p>", "links"=>[], "tags"=>["pap", "PPAR α. Activation", "pde", "5 μ M resveratrol", "docking mode simulation", "feedforward activation loop", "IC 50", "PPAR α"], "article_id"=>1350643, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Yoshie Takizawa", "Rieko Nakata", "Kiyoshi Fukuhara", "Hiroshi Yamashita", "Hideo Kubodera", "Hiroyasu Inoue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120865.g002", "stats"=>{"downloads"=>6, "page_views"=>28, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Docking_models_and_analysis_of_PPAR_945_residues_required_for_binding_to_resveratrol_/1350643", "title"=>"Docking models and analysis of PPARα residues required for binding to resveratrol.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-23 04:42:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1982008"], "description"=>"<p>RT-qPCR was used to determine the mRNA levels of the indicated genes in liver samples from wild-type (WT; filled columns) and PPARα-knockout (PPARα KO; open columns) mice fed the control AIN-93G diet (C) or the same diet supplemented with 0.04% 4-PAP for 8 weeks. Data represent the mean ± SD from 7–8 mice in each group (WT) and from 4 mice in each group (PPARα KO). Data were statistically evaluated using the unpaired two-way ANOVA with post-hoc Bonferroni multiple comparison test. *<i>p</i> < 0.05 compared with wild-type mice fed the control diet. <sup>#</sup><i>p</i> < 0.05 compared with wild-type mice fed the 4-PAP-supplemented diet. For each mRNA, data were normalized to the expression levels in wild-type mice fed the control diet.</p>", "links"=>[], "tags"=>["pap", "PPAR α. Activation", "pde", "5 μ M resveratrol", "docking mode simulation", "feedforward activation loop", "IC 50", "PPAR α"], "article_id"=>1350644, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Yoshie Takizawa", "Rieko Nakata", "Kiyoshi Fukuhara", "Hiroshi Yamashita", "Hideo Kubodera", "Hiroyasu Inoue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120865.g003", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_4_PAP_induces_PPAR_dependent_genes_and_SIRT1_in_vivo_/1350644", "title"=>"4-PAP induces PPARα-dependent genes and SIRT1 <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-23 04:42:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1982011"], "description"=>"<p>(A) The dose-dependent activation of PPARα by resveratrol, T4HS and 4-PAP in BAECs transiently transfected with PPRE-luc, GS-hPPARα, and pSV-β-gal. Following transfection, the cells were incubated for 24 h with resveratrol, T4HS or 4-PAP at the indicated concentrations. Data were normalized to the β-galactosidase standard and represent the mean ± SD of three independent wells of cells. The right graph corresponds to the lower area marked by a dashed rectangle in left graph. (B) cAMP-dependent enhancement of PPARα activation by resveratrol, T4HS or 4-PAP. BAECs transiently transfected with PPRE-luc, GS-hPPARα, and pSV-β-gal were incubated for 24 h with 5 μM compounds in the presence or absence of 25 μM rolipram, a PDE4 inhibitor, or 25 μM forskolin, an adenylate cyclase activator. Luciferase data were normalized to the β-galactosidase standard and represent the mean ± SD of three independent wells. *<i>p</i> < 0.05, ***<i>p</i> < 0.001 (unpaired <i>t</i>-test) compared with control cells treated with the same compound. (C) The inhibition of PDE by resveratrol, T4HS, and rolipram. Data represent the mean ± SD of three independent wells of cells. Similar results were obtained by two additional experiments. The IC<sub>50</sub> values are shown in the Table. ***<i>p</i> < 0.001 (unpaired <i>t</i>-test) compared with rolipram. <sup>###</sup><i>p</i> < 0.001 (unpaired <i>t</i>-test) compared with resveratrol. Similar results were obtained by two additional experiments in (A-C).</p>", "links"=>[], "tags"=>["pap", "PPAR α. Activation", "pde", "5 μ M resveratrol", "docking mode simulation", "feedforward activation loop", "IC 50", "PPAR α"], "article_id"=>1350647, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Yoshie Takizawa", "Rieko Nakata", "Kiyoshi Fukuhara", "Hiroshi Yamashita", "Hideo Kubodera", "Hiroyasu Inoue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120865.g004", "stats"=>{"downloads"=>3, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_PDE_enhances_the_activation_of_PPAR_945_by_resveratrol_especially_at_higher_doses_/1350647", "title"=>"Inhibition of PDE enhances the activation of PPARα by resveratrol, especially at higher doses.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-23 04:42:33"}

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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