Nox4 and Duox1/2 Mediate Redox Activation of Mesenchymal Cell Migration by PDGF
Platelet derived growth factor (PDGF) orchestrates wound healing and tissue regeneration by regulating recruitment of the precursor mesenchymal stromal cells (MSC) and fibroblasts. PDGF stimulates generation of hydrogen peroxide that is required for cell migration, but the sources and intracellular...
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| Veröffentlicht in: | PloS one 2016-04, Vol.11 (4), p.e0154157-e0154157 |
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| creator | Tyurin-Kuzmin, Pyotr A Zhdanovskaya, Nadezhda D Sukhova, Anna A Sagaradze, George D Albert, Eugene A Ageeva, Ludmila V Sharonov, George V Vorotnikov, Alexander V Tkachuk, Vsevolod A |
| description | Platelet derived growth factor (PDGF) orchestrates wound healing and tissue regeneration by regulating recruitment of the precursor mesenchymal stromal cells (MSC) and fibroblasts. PDGF stimulates generation of hydrogen peroxide that is required for cell migration, but the sources and intracellular targets of H2O2 remain obscure. Here we demonstrate sustained live responses of H2O2 to PDGF and identify PKB/Akt, but not Erk1/2, as the target for redox regulation in cultured 3T3 fibroblasts and MSC. Apocynin, cell-permeable catalase and LY294002 inhibited PDGF-induced migration and mitotic activity of these cells indicating involvement of PI3-kinase pathway and H2O2. Real-time PCR revealed Nox4 and Duox1/2 as the potential sources of H2O2. Silencing of Duox1/2 in fibroblasts or Nox4 in MSC reduced PDGF-stimulated intracellular H2O2, PKB/Akt phosphorylation and migration, but had no such effect on Erk1/2. In contrast to PDGF, EGF failed to increase cytoplasmic H2O2, phosphorylation of PKB/Akt and migration of fibroblasts and MSC, confirming the critical impact of redox signaling. We conclude that PDGF-induced migration of mesenchymal cells requires Nox4 and Duox1/2 enzymes, which mediate redox-sensitive activation of PI3-kinase pathway and PKB/Akt. |
| doi_str_mv | 10.1371/journal.pone.0154157 |
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PDGF stimulates generation of hydrogen peroxide that is required for cell migration, but the sources and intracellular targets of H2O2 remain obscure. Here we demonstrate sustained live responses of H2O2 to PDGF and identify PKB/Akt, but not Erk1/2, as the target for redox regulation in cultured 3T3 fibroblasts and MSC. Apocynin, cell-permeable catalase and LY294002 inhibited PDGF-induced migration and mitotic activity of these cells indicating involvement of PI3-kinase pathway and H2O2. Real-time PCR revealed Nox4 and Duox1/2 as the potential sources of H2O2. Silencing of Duox1/2 in fibroblasts or Nox4 in MSC reduced PDGF-stimulated intracellular H2O2, PKB/Akt phosphorylation and migration, but had no such effect on Erk1/2. In contrast to PDGF, EGF failed to increase cytoplasmic H2O2, phosphorylation of PKB/Akt and migration of fibroblasts and MSC, confirming the critical impact of redox signaling. We conclude that PDGF-induced migration of mesenchymal cells requires Nox4 and Duox1/2 enzymes, which mediate redox-sensitive activation of PI3-kinase pathway and PKB/Akt.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0154157</identifier><identifier>PMID: 27110716</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; Acetophenones - pharmacology ; Activation ; AKT protein ; Animals ; Biochemistry ; Biology and Life Sciences ; Cardiology ; Catalase ; Cell activation ; Cell adhesion & migration ; Cell culture ; Cell cycle ; Cell migration ; Cell Movement - drug effects ; Chromones - pharmacology ; Dual Oxidases ; Epidermal growth factor ; Extracellular signal-regulated kinase ; Fibroblasts ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Hydrogen ; Hydrogen peroxide ; Hydrogen Peroxide - metabolism ; Intracellular ; Kinases ; Medicine ; Medicine and Health Sciences ; Mesenchymal Stem Cells - cytology ; Mesenchymal Stem Cells - drug effects ; Mesenchymal Stem Cells - metabolism ; Mesenchyme ; Mice ; Mitogen-Activated Protein Kinase 1 - genetics ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - genetics ; Mitogen-Activated Protein Kinase 3 - metabolism ; Morpholines - pharmacology ; NADPH Oxidase 4 ; NADPH Oxidases - antagonists & inhibitors ; NADPH Oxidases - genetics ; NADPH Oxidases - metabolism ; NIH 3T3 Cells ; NOX4 protein ; Oxidation-Reduction ; Oxidative stress ; Phosphatidylinositol 3-Kinase - genetics ; Phosphatidylinositol 3-Kinase - metabolism ; Phosphorylation ; Physical Sciences ; Platelet-derived growth factor ; Platelet-Derived Growth Factor - antagonists & inhibitors ; Platelet-Derived Growth Factor - pharmacology ; Primary Cell Culture ; Proteins ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Recruitment ; Regeneration ; Regeneration (Biology) ; Research and Analysis Methods ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Signal Transduction ; Signaling ; Smooth muscle ; Stem cells ; Stromal cells ; Tissue engineering ; Wound healing</subject><ispartof>PloS one, 2016-04, Vol.11 (4), p.e0154157-e0154157</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Tyurin-Kuzmin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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PDGF stimulates generation of hydrogen peroxide that is required for cell migration, but the sources and intracellular targets of H2O2 remain obscure. Here we demonstrate sustained live responses of H2O2 to PDGF and identify PKB/Akt, but not Erk1/2, as the target for redox regulation in cultured 3T3 fibroblasts and MSC. Apocynin, cell-permeable catalase and LY294002 inhibited PDGF-induced migration and mitotic activity of these cells indicating involvement of PI3-kinase pathway and H2O2. Real-time PCR revealed Nox4 and Duox1/2 as the potential sources of H2O2. Silencing of Duox1/2 in fibroblasts or Nox4 in MSC reduced PDGF-stimulated intracellular H2O2, PKB/Akt phosphorylation and migration, but had no such effect on Erk1/2. In contrast to PDGF, EGF failed to increase cytoplasmic H2O2, phosphorylation of PKB/Akt and migration of fibroblasts and MSC, confirming the critical impact of redox signaling. We conclude that PDGF-induced migration of mesenchymal cells requires Nox4 and Duox1/2 enzymes, which mediate redox-sensitive activation of PI3-kinase pathway and PKB/Akt.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Acetophenones - pharmacology</subject><subject>Activation</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Biology and Life Sciences</subject><subject>Cardiology</subject><subject>Catalase</subject><subject>Cell activation</subject><subject>Cell adhesion & migration</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Chromones - pharmacology</subject><subject>Dual Oxidases</subject><subject>Epidermal growth factor</subject><subject>Extracellular signal-regulated kinase</subject><subject>Fibroblasts</subject><subject>Gene Expression Regulation</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hydrogen</subject><subject>Hydrogen peroxide</subject><subject>Hydrogen Peroxide - 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genetics</subject><subject>Phosphatidylinositol 3-Kinase - metabolism</subject><subject>Phosphorylation</subject><subject>Physical Sciences</subject><subject>Platelet-derived growth factor</subject><subject>Platelet-Derived Growth Factor - antagonists & inhibitors</subject><subject>Platelet-Derived Growth Factor - pharmacology</subject><subject>Primary Cell Culture</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Recruitment</subject><subject>Regeneration</subject><subject>Regeneration (Biology)</subject><subject>Research and Analysis Methods</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Smooth muscle</subject><subject>Stem cells</subject><subject>Stromal cells</subject><subject>Tissue engineering</subject><subject>Wound healing</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1v0zAUhiMEYqPwDxBEQkJw0c7fSW6Qqo6NShtF4-PWOolPWk9pXOJkav89Ls2mBu0C-cLWOc95j338RtFrSiaUJ_Ts1nVNDdVk42qcECoFlcmT6JRmnI0VI_zp0fkkeuH9LSGSp0o9j05YQilJqDqNFl_dVsRQm_i8c1t6xuJrNBZajG_QuG08LVp7B611dezKkPNYF6vdGqp4hlUVX9tlc8jmu_jb-eXFy-hZCZXHV_0-in5efP4x-zK-WlzOZ9OrcaEy1o5LmZUMmaI0BWpShpLlOU9YligEleWGSDSy5AnPMkkhMTnBnHEDDAynKeej6O1Bd1M5r_tZeE2TVJCUCEkCMT8QxsGt3jR2Dc1OO7D6b8A1Sw1Na4sKtRJScZlAATwXgCYVBkxOqeSKGhEuMYo-9d26fI2mwLptoBqIDjO1Xemlu9MiFYJyGQQ-9AKN-92hb_Xa-iJMEGp03eHeicgyte_17h_08df11BLCA2xdutC32IvqqZBcMCUzFajJI1RYBte2CMYpbYgPCj4OCgLT4rZdQue9nn-_-X928WvIvj9iVwhVu_Ku6vbW8UNQHMCicd43WD4MmRK99_39NPTe97r3fSh7c_xBD0X3Rud_AAM7-lk</recordid><startdate>20160425</startdate><enddate>20160425</enddate><creator>Tyurin-Kuzmin, Pyotr A</creator><creator>Zhdanovskaya, Nadezhda D</creator><creator>Sukhova, Anna A</creator><creator>Sagaradze, George D</creator><creator>Albert, Eugene A</creator><creator>Ageeva, Ludmila V</creator><creator>Sharonov, George V</creator><creator>Vorotnikov, Alexander V</creator><creator>Tkachuk, Vsevolod A</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-1460-971X</orcidid></search><sort><creationdate>20160425</creationdate><title>Nox4 and Duox1/2 Mediate Redox Activation of Mesenchymal Cell Migration by PDGF</title><author>Tyurin-Kuzmin, Pyotr A ; Zhdanovskaya, Nadezhda D ; Sukhova, Anna A ; Sagaradze, George D ; Albert, Eugene A ; Ageeva, Ludmila V ; Sharonov, George V ; Vorotnikov, Alexander V ; Tkachuk, Vsevolod A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-f59f2e26118a1d82e52bb372976ea69bd05ed5f3739951a7db0eb23da2ad31833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Acetophenones - 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genetics</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Recruitment</topic><topic>Regeneration</topic><topic>Regeneration (Biology)</topic><topic>Research and Analysis Methods</topic><topic>RNA, Small Interfering - genetics</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Smooth muscle</topic><topic>Stem cells</topic><topic>Stromal cells</topic><topic>Tissue engineering</topic><topic>Wound healing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tyurin-Kuzmin, Pyotr A</creatorcontrib><creatorcontrib>Zhdanovskaya, Nadezhda D</creatorcontrib><creatorcontrib>Sukhova, Anna A</creatorcontrib><creatorcontrib>Sagaradze, George D</creatorcontrib><creatorcontrib>Albert, Eugene A</creatorcontrib><creatorcontrib>Ageeva, Ludmila V</creatorcontrib><creatorcontrib>Sharonov, George V</creatorcontrib><creatorcontrib>Vorotnikov, Alexander V</creatorcontrib><creatorcontrib>Tkachuk, Vsevolod A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tyurin-Kuzmin, Pyotr A</au><au>Zhdanovskaya, Nadezhda D</au><au>Sukhova, Anna A</au><au>Sagaradze, George D</au><au>Albert, Eugene A</au><au>Ageeva, Ludmila V</au><au>Sharonov, George V</au><au>Vorotnikov, Alexander V</au><au>Tkachuk, Vsevolod A</au><au>Pintus, Gianfranco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nox4 and Duox1/2 Mediate Redox Activation of Mesenchymal Cell Migration by PDGF</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-04-25</date><risdate>2016</risdate><volume>11</volume><issue>4</issue><spage>e0154157</spage><epage>e0154157</epage><pages>e0154157-e0154157</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Platelet derived growth factor (PDGF) orchestrates wound healing and tissue regeneration by regulating recruitment of the precursor mesenchymal stromal cells (MSC) and fibroblasts. PDGF stimulates generation of hydrogen peroxide that is required for cell migration, but the sources and intracellular targets of H2O2 remain obscure. Here we demonstrate sustained live responses of H2O2 to PDGF and identify PKB/Akt, but not Erk1/2, as the target for redox regulation in cultured 3T3 fibroblasts and MSC. Apocynin, cell-permeable catalase and LY294002 inhibited PDGF-induced migration and mitotic activity of these cells indicating involvement of PI3-kinase pathway and H2O2. Real-time PCR revealed Nox4 and Duox1/2 as the potential sources of H2O2. Silencing of Duox1/2 in fibroblasts or Nox4 in MSC reduced PDGF-stimulated intracellular H2O2, PKB/Akt phosphorylation and migration, but had no such effect on Erk1/2. In contrast to PDGF, EGF failed to increase cytoplasmic H2O2, phosphorylation of PKB/Akt and migration of fibroblasts and MSC, confirming the critical impact of redox signaling. We conclude that PDGF-induced migration of mesenchymal cells requires Nox4 and Duox1/2 enzymes, which mediate redox-sensitive activation of PI3-kinase pathway and PKB/Akt.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27110716</pmid><doi>10.1371/journal.pone.0154157</doi><orcidid>https://orcid.org/0000-0002-1460-971X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-04, Vol.11 (4), p.e0154157-e0154157 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1784080450 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 1-Phosphatidylinositol 3-kinase Acetophenones - pharmacology Activation AKT protein Animals Biochemistry Biology and Life Sciences Cardiology Catalase Cell activation Cell adhesion & migration Cell culture Cell cycle Cell migration Cell Movement - drug effects Chromones - pharmacology Dual Oxidases Epidermal growth factor Extracellular signal-regulated kinase Fibroblasts Gene Expression Regulation HEK293 Cells Humans Hydrogen Hydrogen peroxide Hydrogen Peroxide - metabolism Intracellular Kinases Medicine Medicine and Health Sciences Mesenchymal Stem Cells - cytology Mesenchymal Stem Cells - drug effects Mesenchymal Stem Cells - metabolism Mesenchyme Mice Mitogen-Activated Protein Kinase 1 - genetics Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - genetics Mitogen-Activated Protein Kinase 3 - metabolism Morpholines - pharmacology NADPH Oxidase 4 NADPH Oxidases - antagonists & inhibitors NADPH Oxidases - genetics NADPH Oxidases - metabolism NIH 3T3 Cells NOX4 protein Oxidation-Reduction Oxidative stress Phosphatidylinositol 3-Kinase - genetics Phosphatidylinositol 3-Kinase - metabolism Phosphorylation Physical Sciences Platelet-derived growth factor Platelet-Derived Growth Factor - antagonists & inhibitors Platelet-Derived Growth Factor - pharmacology Primary Cell Culture Proteins Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Recruitment Regeneration Regeneration (Biology) Research and Analysis Methods RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Signal Transduction Signaling Smooth muscle Stem cells Stromal cells Tissue engineering Wound healing |
| title | Nox4 and Duox1/2 Mediate Redox Activation of Mesenchymal Cell Migration by PDGF |
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