Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells
Identifieur interne : 001226 ( Pmc/Curation ); précédent : 001225; suivant : 001227Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells
Auteurs : Hui-Chi Lai [Taïwan] ; Ming-Jiuan Wu [Taïwan] ; Pei-Yi Chen [Taïwan] ; Ting-Ting Sheu [Taïwan] ; Szu-Ping Chiu [Taïwan] ; Meng-Han Lin [Taïwan] ; Chi-Tang Ho [États-Unis] ; Jui-Hung Yen [Taïwan]Source :
- PLoS ONE [ 1932-6203 ] ; 2011.
Abstract
5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5-OH-HxMF), a hydroxylated polymethoxyflavone, is found exclusively in the Citrus genus, particularly in the peels of sweet orange. In this research, we report the first investigation of the neurotrophic effects and mechanism of 5-OH-HxMF in PC12 pheochromocytoma cells. We found that 5-OH-HxMF can effectively induce PC12 neurite outgrowth accompanied with the expression of neuronal differentiation marker protein growth-associated protein-43(GAP-43). 5-OH-HxMF caused the enhancement of cyclic AMP response element binding protein (CREB) phosphorylation, c-fos gene expression and CRE-mediated transcription, which was inhibited by 2-naphthol AS-E phosphate (KG-501), a specific antagonist for the CREB-CBP complex formation. Moreover, 5-OH-HxMF-induced both CRE transcription activity and neurite outgrowth were inhibited by adenylate cyclase and protein kinase A (PKA) inhibitor, but not MEK1/2, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K) or calcium/calmodulin-dependent protein kinase (CaMK) inhibitor. Consistently, 5-OH-HxMF treatment increased the intracellular cAMP level and downstream component, PKA activity. We also found that addition of K252a, a TrKA antagonist, significantly inhibited NGF- but not 5-OH-HxMF-induced neurite outgrowth. These results reveal for the first time that 5-OH-HxMF is an effective neurotrophic agent and its effect is mainly through a cAMP/PKA-dependent, but TrKA-independent, signaling pathway coupling with CRE-mediated gene transcription. A PKC-dependent and CREB-independent pathway was also involved in its neurotrophic action.
Url:
DOI: 10.1371/journal.pone.0028280
PubMed: 22140566
PubMed Central: 3226691
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells</title><author><name sortKey="Lai, Hui Chi" sort="Lai, Hui Chi" uniqKey="Lai H" first="Hui-Chi" last="Lai">Hui-Chi Lai</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien</wicri:regionArea></affiliation></author><author><name sortKey="Wu, Ming Jiuan" sort="Wu, Ming Jiuan" uniqKey="Wu M" first="Ming-Jiuan" last="Wu">Ming-Jiuan Wu</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Pei Yi" sort="Chen, Pei Yi" uniqKey="Chen P" first="Pei-Yi" last="Chen">Pei-Yi Chen</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institute of Medical Science, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Medical Science, Tzu Chi University, Hualien</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien</wicri:regionArea></affiliation></author><author><name sortKey="Sheu, Ting Ting" sort="Sheu, Ting Ting" uniqKey="Sheu T" first="Ting-Ting" last="Sheu">Ting-Ting Sheu</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Institute of Microbiology, Immunology and Biochemistry, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Microbiology, Immunology and Biochemistry, Tzu Chi University, Hualien</wicri:regionArea></affiliation></author><author><name sortKey="Chiu, Szu Ping" sort="Chiu, Szu Ping" uniqKey="Chiu S" first="Szu-Ping" last="Chiu">Szu-Ping Chiu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien</wicri:regionArea></affiliation></author><author><name sortKey="Lin, Meng Han" sort="Lin, Meng Han" uniqKey="Lin M" first="Meng-Han" last="Lin">Meng-Han 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type="wicri:Area/Pmc/Curation">001226</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells</title><author><name sortKey="Lai, Hui Chi" sort="Lai, Hui Chi" uniqKey="Lai H" first="Hui-Chi" last="Lai">Hui-Chi Lai</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien</wicri:regionArea></affiliation></author><author><name sortKey="Wu, Ming Jiuan" sort="Wu, Ming Jiuan" uniqKey="Wu M" first="Ming-Jiuan" last="Wu">Ming-Jiuan Wu</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Pei Yi" sort="Chen, Pei Yi" uniqKey="Chen P" first="Pei-Yi" last="Chen">Pei-Yi Chen</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institute of Medical Science, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Medical Science, Tzu Chi University, Hualien</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien</wicri:regionArea></affiliation></author><author><name sortKey="Sheu, Ting Ting" sort="Sheu, Ting Ting" uniqKey="Sheu T" first="Ting-Ting" last="Sheu">Ting-Ting Sheu</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Institute of Microbiology, Immunology and Biochemistry, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Microbiology, Immunology and Biochemistry, Tzu Chi University, Hualien</wicri:regionArea></affiliation></author><author><name sortKey="Chiu, Szu Ping" sort="Chiu, Szu Ping" uniqKey="Chiu S" first="Szu-Ping" last="Chiu">Szu-Ping Chiu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien</wicri:regionArea></affiliation></author><author><name sortKey="Lin, Meng Han" sort="Lin, Meng Han" uniqKey="Lin M" first="Meng-Han" last="Lin">Meng-Han Lin</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan</wicri:regionArea></affiliation></author><author><name sortKey="Ho, Chi Tang" sort="Ho, Chi Tang" uniqKey="Ho C" first="Chi-Tang" last="Ho">Chi-Tang Ho</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Department of Food Science, Rutgers University, New Brunswick, New Jersey, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Food Science, Rutgers University, New Brunswick, New Jersey</wicri:regionArea></affiliation></author><author><name sortKey="Yen, Jui Hung" sort="Yen, Jui Hung" uniqKey="Yen J" first="Jui-Hung" last="Yen">Jui-Hung Yen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institute of Medical Science, Tzu Chi University, Hualien, Taiwan</addr-line></nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Medical Science, Tzu Chi University, Hualien</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5-OH-HxMF), a hydroxylated polymethoxyflavone, is found exclusively in the Citrus genus, particularly in the peels of sweet orange. In this research, we report the first investigation of the neurotrophic effects and mechanism of 5-OH-HxMF in PC12 pheochromocytoma cells. We found that 5-OH-HxMF can effectively induce PC12 neurite outgrowth accompanied with the expression of neuronal differentiation marker protein growth-associated protein-43(GAP-43). 5-OH-HxMF caused the enhancement of cyclic AMP response element binding protein (CREB) phosphorylation, c-fos gene expression and CRE-mediated transcription, which was inhibited by 2-naphthol AS-E phosphate (KG-501), a specific antagonist for the CREB-CBP complex formation. Moreover, 5-OH-HxMF-induced both CRE transcription activity and neurite outgrowth were inhibited by adenylate cyclase and protein kinase A (PKA) inhibitor, but not MEK1/2, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K) or calcium/calmodulin-dependent protein kinase (CaMK) inhibitor. Consistently, 5-OH-HxMF treatment increased the intracellular cAMP level and downstream component, PKA activity. We also found that addition of K252a, a TrKA antagonist, significantly inhibited NGF- but not 5-OH-HxMF-induced neurite outgrowth. These results reveal for the first time that 5-OH-HxMF is an effective neurotrophic agent and its effect is mainly through a cAMP/PKA-dependent, but TrKA-independent, signaling pathway coupling with CRE-mediated gene transcription. A PKC-dependent and CREB-independent pathway was also involved in its neurotrophic action.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bui, Nt" uniqKey="Bui N">NT Bui</name></author><author><name sortKey="Konig, Hg" uniqKey="Konig H">HG Konig</name></author><author><name sortKey="Culmsee, C" uniqKey="Culmsee C">C Culmsee</name></author><author><name sortKey="Bauerbach, E" uniqKey="Bauerbach E">E Bauerbach</name></author><author><name sortKey="Poppe, M" uniqKey="Poppe M">M Poppe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schulte Herbruggen, O" uniqKey="Schulte Herbruggen O">O Schulte-Herbruggen</name></author><author><name sortKey="Jockers Scherubl, Mc" uniqKey="Jockers Scherubl M">MC Jockers-Scherubl</name></author><author><name sortKey="Hellweg, R" uniqKey="Hellweg R">R Hellweg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Levy, Ys" uniqKey="Levy 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22140566</article-id><article-id pub-id-type="pmc">3226691</article-id><article-id pub-id-type="publisher-id">PONE-D-11-11986</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0028280</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Molecular Cell Biology</subject><subj-group><subject>Signal Transduction</subject><subj-group><subject>Signaling in Cellular Processes</subject><subj-group><subject>Creb Signaling</subject></subj-group></subj-group><subj-group><subject>Signaling in Selected Disciplines</subject><subj-group><subject>Neurological Signaling</subject></subj-group></subj-group></subj-group></subj-group><subj-group><subject>Neuroscience</subject><subj-group><subject>Cellular Neuroscience</subject><subject>Neurochemistry</subject><subject>Neurotransmitters</subject></subj-group></subj-group><subj-group><subject>Plant Science</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Chemistry</subject><subj-group><subject>Phytochemistry</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject><subj-group><subject>Neurology</subject><subj-group><subject>Neuropharmacology</subject></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells</article-title><alt-title alt-title-type="running-head">5-OH-HxMF Promotes Neurite Outgrowth in PC12 Cells</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lai</surname><given-names>Hui-Chi</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Ming-Jiuan</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Pei-Yi</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sheu</surname><given-names>Ting-Ting</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chiu</surname><given-names>Szu-Ping</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lin</surname><given-names>Meng-Han</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ho</surname><given-names>Chi-Tang</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yen</surname><given-names>Jui-Hung</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Institute of Medical Science, Tzu Chi University, Hualien, Taiwan</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Institute of Microbiology, Immunology and Biochemistry, Tzu Chi University, Hualien, Taiwan</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Department of Food Science, Rutgers University, New Brunswick, New Jersey, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Chu</surname><given-names>Charleen T.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">University of Pittsburgh, United States of America</aff><author-notes><corresp id="cor1">* E-mail: <email>imyenjh@mail.tcu.edu.tw</email></corresp><fn fn-type="con"><p>Conceived and designed the experiments: MJW PYC JHY. Performed the experiments: HCL PYC SPC MHL. Analyzed the data: HCL JHY. Contributed reagents/materials/analysis tools: MJW TTS CTH JHY. Wrote the paper: MJW CTH JHY.</p></fn></author-notes><pub-date pub-type="collection"><year>2011</year></pub-date><pub-date pub-type="epub"><day>29</day><month>11</month><year>2011</year></pub-date><volume>6</volume><issue>11</issue><elocation-id>e28280</elocation-id><history><date date-type="received"><day>27</day><month>6</month><year>2011</year></date><date date-type="accepted"><day>4</day><month>11</month><year>2011</year></date></history><permissions><copyright-statement>Lai, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</copyright-statement><copyright-year>2011</copyright-year></permissions><abstract><p>5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5-OH-HxMF), a hydroxylated polymethoxyflavone, is found exclusively in the Citrus genus, particularly in the peels of sweet orange. In this research, we report the first investigation of the neurotrophic effects and mechanism of 5-OH-HxMF in PC12 pheochromocytoma cells. We found that 5-OH-HxMF can effectively induce PC12 neurite outgrowth accompanied with the expression of neuronal differentiation marker protein growth-associated protein-43(GAP-43). 5-OH-HxMF caused the enhancement of cyclic AMP response element binding protein (CREB) phosphorylation, c-fos gene expression and CRE-mediated transcription, which was inhibited by 2-naphthol AS-E phosphate (KG-501), a specific antagonist for the CREB-CBP complex formation. Moreover, 5-OH-HxMF-induced both CRE transcription activity and neurite outgrowth were inhibited by adenylate cyclase and protein kinase A (PKA) inhibitor, but not MEK1/2, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K) or calcium/calmodulin-dependent protein kinase (CaMK) inhibitor. Consistently, 5-OH-HxMF treatment increased the intracellular cAMP level and downstream component, PKA activity. We also found that addition of K252a, a TrKA antagonist, significantly inhibited NGF- but not 5-OH-HxMF-induced neurite outgrowth. These results reveal for the first time that 5-OH-HxMF is an effective neurotrophic agent and its effect is mainly through a cAMP/PKA-dependent, but TrKA-independent, signaling pathway coupling with CRE-mediated gene transcription. A PKC-dependent and CREB-independent pathway was also involved in its neurotrophic action.</p></abstract><counts><page-count count="14"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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