Luteolin and Apigenin Attenuate 4-Hydroxy-2-Nonenal-Mediated Cell Death through Modulation of UPR, Nrf2-ARE and MAPK Pathways in PC12 Cells
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{"title"=>"Luteolin and apigenin attenuate 4-hydroxy- 2-nonenal-mediated cell death through modulation of UPR, Nrf2-ARE and MAPK pathways in PC12 cells", "type"=>"journal", "authors"=>[{"first_name"=>"Pei Shan", "last_name"=>"Wu", "scopus_author_id"=>"56780815100"}, {"first_name"=>"Jui Hung", "last_name"=>"Yen", "scopus_author_id"=>"56638734700"}, {"first_name"=>"Mei Chun", "last_name"=>"Kou", "scopus_author_id"=>"23389760300"}, {"first_name"=>"Ming Jiuan", "last_name"=>"Wu", "scopus_author_id"=>"8665258300"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"26087007", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0130599", "issn"=>"19326203", "scopus"=>"2-s2.0-84939218232", "pui"=>"605585872", "sgr"=>"84939218232"}, "id"=>"be414935-358f-3a2b-ac90-df4116a5b520", "abstract"=>"Luteolin and apigenin are dietary flavones and exhibit a broad spectrum of biological activities including antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. The lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE) has been implicated as a causative agent in the development of neurodegenerative disorders. This study investigates the cytoprotective effects of luteolin and apigenin against 4-HNE-mediated cytotoxicity in neuronal-like catecholaminergic PC12 cells. Both flavones restored cell viability and repressed caspase-3 and PARP-1 activation in 4-HNE-treated cells. Luteolin also mitigated 4-HNE-mediated LC3 conversion and reactive oxygen species (ROS) production. Luteolin and apigenin up-regulated 4-HNE-mediated unfolded protein response (UPR), leading to an increase in endoplasmic reticulum chaperone GRP78 and decrease in the expression of UPR-targeted pro-apoptotic genes. They also induced the expression of Nrf2-targeted HO-1 and xCT in the absence of 4-HNE, but counteracted their expression in the presence of 4-HNE. Moreover, we found that JNK and p38 MAPK inhibitors significantly antagonized the increase in cell viability induced by luteolin and apigenin. Consistently, enhanced phosphorylation of JNK and p38 MAPK was observed in luteolin- and apigenin-treated cells. In conclusion, this result shows that luteolin and apigenin activate MAPK and Nrf2 signaling, which elicit adaptive cellular stress response pathways, restore 4-HNE-induced ER homeostasis and inhibit cytotoxicity. Luteolin exerts a stronger cytoprotective effect than apigenin possibly due to its higher MAPK, Nrf2 and UPR activation, and ROS scavenging activity.", "link"=>"http://www.mendeley.com/research/luteolin-apigenin-attenuate-4hydroxy-2nonenalmediated-cell-death-through-modulation-upr-nrf2are-mapk", "reader_count"=>8, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>1, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>1, "Other"=>1, "Student > Master"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>1, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>1, "Other"=>1, "Student > Master"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>4, "Medicine and Dentistry"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2124733"], "description"=>"<p>(<b>A</b>) Western blot analysis of ATF4 and eIF2α phosphorylation in lysates obtained from PC12 cells incubated in the presence of vehicle only (V), or presence of 25 μM HNE plus vehicle (Veh), or co-treatment with 20 μM luteolin or apigenin for 2 h. (<b>B</b>) Effects of flavones on XBP1 splicing. PC12 cells were treated with luteolin and apigenin (20 μM) 30 min prior to 4-HNE (25 μM) treatment for 4 h at 37°. RNA was prepared and semi-quantitative RT-PCR was used for the analysis of mRNA levels of XBP1s and XBP1u, as described in Materials and Methods. (<b>C</b>) Western blot analysis of GRP78 in cell lysates prepared from PC12 cells, which were pretreated with luteolin or apigenin (20 μM) for 30 min followed by 4-HNE for 6 h. Immunoblots and polyacrylamide gels were then analyzed using Phoretix Gel Analysis Software as described under Materials and methods. Data represent the mean ± SD of three independent experiments. **, <i>p</i><0.01 represents significant differences compared with vehicle control (without oxidant). ##, <i>p</i><0.01 represents significant differences compared with the 4-HNE-treated vehicle group.</p>", "links"=>[], "tags"=>["parp", "endoplasmic reticulum chaperone GRP 78", "stress response pathways", "jnk", "p 38 MAPK", "ho", "PC 12 Cells Luteolin", "ros", "upr", "expression", "Reactive oxygen species", "apigenin", "hne", "luteolin", "er", "cell viability", "lc", "p 38 MAPK inhibitors", "Nrf 2"], "article_id"=>1453248, "categories"=>["Uncategorised"], "users"=>["Pei-Shan Wu", "Jui-Hung Yen", "Mei-Chun Kou", "Ming-Jiuan Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130599.g003", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Luteolin_and_apigenin_enhance_4_HNE_mediated_unfolded_protein_response_/1453248", "title"=>"Luteolin and apigenin enhance 4-HNE-mediated unfolded protein response.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-18 02:44:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2124746"], "description"=>"<p>Primary antibodies used in Western blotting.</p>", "links"=>[], "tags"=>["parp", "endoplasmic reticulum chaperone GRP 78", "stress response pathways", "jnk", "p 38 MAPK", "ho", "PC 12 Cells Luteolin", "ros", "upr", "expression", "Reactive oxygen species", "apigenin", "hne", "luteolin", "er", "cell viability", "lc", "p 38 MAPK inhibitors", "Nrf 2"], "article_id"=>1453261, "categories"=>["Uncategorised"], "users"=>["Pei-Shan Wu", "Jui-Hung Yen", "Mei-Chun Kou", "Ming-Jiuan Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130599.t001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Primary_antibodies_used_in_Western_blotting_/1453261", "title"=>"Primary antibodies used in Western blotting.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-06-18 02:44:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2124731"], "description"=>"<p>(<b>A</b>) Structures of 4-HNE, luteolin, apigenin and chrysin (<b>B</b>) Effects of luteolin, apigenin and chrysin on 4-HNE-mediated cytotoxicity. PC12 cells were treated with luteolin, apigenin and chrysin (10 and 20 μM) 30 min prior to 4-HNE (25 and 50 μM) treatment for 16 h at 37x. Cell viability was measured by MTT as described in Materials and Methods. (<b>C</b>) Western blot analysis of active caspase-3 and PARP-1 activation. Cell lysates prepared from those treated with 4-HNE and indicated reagent for 6 h were subjected to SDS-PAGE and then were immunoblotted with antibodies that recognize cleaved caspase-3, PARP-1 and α-tubulin. The blots are representative from one of three independent experiments. Data obtained from immunoblots were then analyzed using Phoretix Gel Analysis Software as described under Materials and methods. Data represent the mean ± SD of three independent experiments. **, <i>p</i><0.01 represents significant differences compared with vehicle control (without 4-HNE). #, <i>p</i><0.05; ##, <i>p</i><0.01 represent significant differences compared with 4-HNE-treated vehicle group.</p>", "links"=>[], "tags"=>["parp", "endoplasmic reticulum chaperone GRP 78", "stress response pathways", "jnk", "p 38 MAPK", "ho", "PC 12 Cells Luteolin", "ros", "upr", "expression", "Reactive oxygen species", "apigenin", "hne", "luteolin", "er", "cell viability", "lc", "p 38 MAPK inhibitors", "Nrf 2"], "article_id"=>1453246, "categories"=>["Uncategorised"], "users"=>["Pei-Shan Wu", "Jui-Hung Yen", "Mei-Chun Kou", "Ming-Jiuan Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130599.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_luteolin_apigenin_and_chrysin_on_4_HNE_mediated_cell_death_caspase_3_activation_and_PARP_1_proteolysis_in_PC12_cells_/1453246", "title"=>"Effects of luteolin, apigenin and chrysin on 4-HNE-mediated cell death, caspase-3 activation and PARP-1 proteolysis in PC12 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-18 02:44:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2124745"], "description"=>"<p>Luteolin can inhibit 4-HNE-induced intracellular ROS over-production and LC3-II accumulation. Luteolin and apigenin modulate 4-HNE-mediated unfolded protein response (UPR), leading to an increase in endoplasmic reticulum chaperone GRP78 and decrease in the expression of UPR-targeted pro-apoptotic genes. They also induce p38 MAPK activation and counteract the expression of Nrf2-targeted HO-1 and xCT in the presence of 4-HNE. The activation of caspase-3 and PARP-1 are attenuated and cell viability is restored. The dashed lines indicate hypothesis not tested yet.</p>", "links"=>[], "tags"=>["parp", "endoplasmic reticulum chaperone GRP 78", "stress response pathways", "jnk", "p 38 MAPK", "ho", "PC 12 Cells Luteolin", "ros", "upr", "expression", "Reactive oxygen species", "apigenin", "hne", "luteolin", "er", "cell viability", "lc", "p 38 MAPK inhibitors", "Nrf 2"], "article_id"=>1453260, "categories"=>["Uncategorised"], "users"=>["Pei-Shan Wu", "Jui-Hung Yen", "Mei-Chun Kou", "Ming-Jiuan Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130599.g008", "stats"=>{"downloads"=>3, "page_views"=>82, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hypothetic_mechanism_of_luteolin_and_apigenin_in_preventing_4_HNE_mediated_cell_death_in_PC12_cells_/1453260", "title"=>"Hypothetic mechanism of luteolin and apigenin in preventing 4-HNE-mediated cell death in PC12 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-18 02:44:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2124742"], "description"=>"<p>(<b>A</b>) Effects of flavones on MAPK activation. PC12 cells were treated with luteolin or apigenin (20 μM) 30 min prior to 4-HNE (25 μM) treatment for 2 and 4 h at 37°. Cell lysates were prepared and the levels of MAPK activation were analyzed by Western blotting. Immunoblots were then analyzed using Phoretix Gel Analysis Software as described under Materials and methods. Data represent the mean ± SD of three independent experiments. **, <i>p</i><0.01 represents significant differences compared with vehicle control (without oxidant). ##, <i>p</i><0.01 represents significant differences compared with the 4-HNE-treated vehicle group. (<b>B</b>) Effects of inhibition of MAPK activation on cell viability. PC12 cells were pretreated for 30 min with 5 μM ERK (U0126), JNK (SP600125) or p38 MAPK inhibitor (SB203580) and 20 μM luteolin or apigenin was then added 30 min prior to 4-HNE (25 μM) exposure for 16 h. MTT was used to analyze the cell viability. Data represent the mean ± SD of three independent experiments. **<i>p</i><0.01 represents significant differences compared with respective no inhibitor group. ##, <i>p</i><0.01 represents significant differences compared with the 4-HNE-treated vehicle group. Data represent the mean ± SD of three independent experiments.</p>", "links"=>[], "tags"=>["parp", "endoplasmic reticulum chaperone GRP 78", "stress response pathways", "jnk", "p 38 MAPK", "ho", "PC 12 Cells Luteolin", "ros", "upr", "expression", "Reactive oxygen species", "apigenin", "hne", "luteolin", "er", "cell viability", "lc", "p 38 MAPK inhibitors", "Nrf 2"], "article_id"=>1453257, "categories"=>["Uncategorised"], "users"=>["Pei-Shan Wu", "Jui-Hung Yen", "Mei-Chun Kou", "Ming-Jiuan Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130599.g006", "stats"=>{"downloads"=>2, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Contributions_of_MAPK_signaling_pathways_to_the_cytoprotective_effects_of_luteolin_and_apigenin_/1453257", "title"=>"Contributions of MAPK signaling pathways to the cytoprotective effects of luteolin and apigenin.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-18 02:44:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2124739"], "description"=>"<p>(<b>A and B</b>) Luteolin exerts the strongest stimulatory effects on HO-1 and xCT expression. PC12 cells were treated with 20 μM luteolin and apigenin. After 6 h, RNA was prepared and the mRNA expression of HO-1 and xCT was analyzed by RT-Q-PCR and normalized to β-actin, as described in Materials and Methods. Data represent the mean ± SD of three independent experiments. *, <i>p</i><0.05; **, <i>p</i><0.01 represents significant differences compared with vehicle control. After 9 h, total cell lysates were prepared and subjected to Western blotting analysis of HO-1 and α-tubulin, which was used as a loading control. (<b>C-F</b>) Luteolin and apigenin counteract 4-HNE-mediated phase II enzyme expression. PC12 cells were treated with luteolin or apigenin (10 or 20 μM) 30 min prior to 4-HNE (25 μM) treatment. After 4 h, RNA was prepared and the expression of HO-1, xCT and GCLC was analyzed by RT-Q-PCR and normalized to β-actin, as described in Materials and Methods. After 6 h, total cell lysates were prepared and subjected to Western blotting analysis of HO-1 and α-tubulin, which was used as a loading control. Data obtained from immunoblots were then analyzed using Phoretix Gel Analysis Software as described under Materials and methods. The data represent the mean ± SD of three independent experiments. **<i>p</i><0.01 represents significant differences compared with vehicle control (without 4-HNE); #<i>p</i><0.01; ##, <i>p</i><0.01 represent significant differences compared with the 4-HNE-treated vehicle group.</p>", "links"=>[], "tags"=>["parp", "endoplasmic reticulum chaperone GRP 78", "stress response pathways", "jnk", "p 38 MAPK", "ho", "PC 12 Cells Luteolin", "ros", "upr", "expression", "Reactive oxygen species", "apigenin", "hne", "luteolin", "er", "cell viability", "lc", "p 38 MAPK inhibitors", "Nrf 2"], "article_id"=>1453254, "categories"=>["Uncategorised"], "users"=>["Pei-Shan Wu", "Jui-Hung Yen", "Mei-Chun Kou", "Ming-Jiuan Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130599.g005", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_flavones_on_Nrf2_targeted_gene_expression_/1453254", "title"=>"Effects of flavones on Nrf2-targeted gene expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-18 02:44:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2124747", "https://ndownloader.figshare.com/files/2124748", "https://ndownloader.figshare.com/files/2124749", "https://ndownloader.figshare.com/files/2124750", "https://ndownloader.figshare.com/files/2124751"], "description"=>"<div><p>Luteolin and apigenin are dietary flavones and exhibit a broad spectrum of biological activities including antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. The lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE) has been implicated as a causative agent in the development of neurodegenerative disorders. This study investigates the cytoprotective effects of luteolin and apigenin against 4-HNE-mediated cytotoxicity in neuronal-like catecholaminergic PC12 cells. Both flavones restored cell viability and repressed caspase-3 and PARP-1 activation in 4-HNE-treated cells. Luteolin also mitigated 4-HNE-mediated LC3 conversion and reactive oxygen species (ROS) production. Luteolin and apigenin up-regulated 4-HNE-mediated unfolded protein response (UPR), leading to an increase in endoplasmic reticulum chaperone GRP78 and decrease in the expression of UPR-targeted pro-apoptotic genes. They also induced the expression of Nrf2-targeted HO-1 and xCT in the absence of 4-HNE, but counteracted their expression in the presence of 4-HNE. Moreover, we found that JNK and p38 MAPK inhibitors significantly antagonized the increase in cell viability induced by luteolin and apigenin. Consistently, enhanced phosphorylation of JNK and p38 MAPK was observed in luteolin- and apigenin-treated cells. In conclusion, this result shows that luteolin and apigenin activate MAPK and Nrf2 signaling, which elicit adaptive cellular stress response pathways, restore 4-HNE-induced ER homeostasis and inhibit cytotoxicity. Luteolin exerts a stronger cytoprotective effect than apigenin possibly due to its higher MAPK, Nrf2 and UPR activation, and ROS scavenging activity.</p></div>", "links"=>[], "tags"=>["parp", "endoplasmic reticulum chaperone GRP 78", "stress response pathways", "jnk", "p 38 MAPK", "ho", "PC 12 Cells Luteolin", "ros", "upr", "expression", "Reactive oxygen species", "apigenin", "hne", "luteolin", "er", "cell viability", "lc", "p 38 MAPK inhibitors", "Nrf 2"], "article_id"=>1453262, "categories"=>["Uncategorised"], "users"=>["Pei-Shan Wu", "Jui-Hung Yen", "Mei-Chun Kou", "Ming-Jiuan Wu"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0130599.s001", "https://dx.doi.org/10.1371/journal.pone.0130599.s002", "https://dx.doi.org/10.1371/journal.pone.0130599.s003", "https://dx.doi.org/10.1371/journal.pone.0130599.s004", "https://dx.doi.org/10.1371/journal.pone.0130599.s005"], "stats"=>{"downloads"=>13, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Luteolin_and_Apigenin_Attenuate_4_Hydroxy_2_Nonenal_Mediated_Cell_Death_through_Modulation_of_UPR_Nrf2_ARE_and_MAPK_Pathways_in_PC12_Cells_/1453262", "title"=>"Luteolin and Apigenin Attenuate 4-Hydroxy-2-Nonenal-Mediated Cell Death through Modulation of UPR, Nrf2-ARE and MAPK Pathways in PC12 Cells", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-06-18 02:44:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2124744"], "description"=>"<p>PC12 cells were pretreated for 30 min with 5 μM JNK (SP600125) or p38 MAPK inhibitor (SB203580) and 20 μM luteolin or apigenin was then added 30 min prior to 4-HNE (25 μM) exposure for 4 h. The mRNA expression of CHOP, HO-1 and xCT was analyzed by RT-Q-PCR and normalized to β-actin, as described in Materials and Methods. Data represent the mean ± SD of three independent experiments. **<i>p</i><0.01 represents significant differences compared with respective no inhibitor group. ##, <i>p</i><0.01 represents significant differences compared with the 4-HNE-treated vehicle group.</p>", "links"=>[], "tags"=>["parp", "endoplasmic reticulum chaperone GRP 78", "stress response pathways", "jnk", "p 38 MAPK", "ho", "PC 12 Cells Luteolin", "ros", "upr", "expression", "Reactive oxygen species", "apigenin", "hne", "luteolin", "er", "cell viability", "lc", "p 38 MAPK inhibitors", "Nrf 2"], "article_id"=>1453259, "categories"=>["Uncategorised"], "users"=>["Pei-Shan Wu", "Jui-Hung Yen", "Mei-Chun Kou", "Ming-Jiuan Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130599.g007", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_JNK_and_p38_MAPK_inhibitors_on_CHOP_HO_1_and_xCT_expression_in_response_to_4_HNE_/1453259", "title"=>"Effects of JNK and p38 MAPK inhibitors on CHOP, HO-1 and xCT expression in response to 4-HNE.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-18 02:44:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2124732"], "description"=>"<p>(<b>A</b>) Western blot analysis of conversion of LC3B. PC12 cells were treated with luteolin, apigenin and chrysin (20 μM) 30 min prior to 4-HNE (25 μM) treatment in serum-free medium for 6 h at 37°. Cell lysates were prepared and were subjected to SDS-PAGE. Immunoblotting was then carried out using an anti-LC3B or anti-α-tubulin antibody. The blots are representative from one of three independent experiments. Data obtained from immunoblots were then analyzed using Phoretix Gel Analysis Software as described under Materials and methods. (<b>B</b>) Intracellular ROS production was measured by DCFDA as described in Materials and Methods. Data represent the mean ± SD of three independent experiments. **, <i>p</i><0.01 represents significant differences compared with vehicle control (without oxidant). ##, <i>p</i><0.01 represents significant differences compared with the 4-HNE-treated vehicle group.</p>", "links"=>[], "tags"=>["parp", "endoplasmic reticulum chaperone GRP 78", "stress response pathways", "jnk", "p 38 MAPK", "ho", "PC 12 Cells Luteolin", "ros", "upr", "expression", "Reactive oxygen species", "apigenin", "hne", "luteolin", "er", "cell viability", "lc", "p 38 MAPK inhibitors", "Nrf 2"], "article_id"=>1453247, "categories"=>["Uncategorised"], "users"=>["Pei-Shan Wu", "Jui-Hung Yen", "Mei-Chun Kou", "Ming-Jiuan Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130599.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_luteolin_apigenin_and_chrysin_on_4_HNE_mediated_LC3_conversion_and_ROS_overproduction_in_PC12_cells_/1453247", "title"=>"Effects of luteolin, apigenin and chrysin on 4-HNE-mediated LC3 conversion and ROS overproduction in PC12 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-18 02:44:40"}

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  • {"unique-ip"=>"12", "full-text"=>"10", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"11", "full-text"=>"13", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}

Relative Metric

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