Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis
Histone acetylation plays a major role in epigenetic regulation of gene expression. Monocyte-derived macrophages express functional NADPH oxidase 5 (Nox5) that contributes to oxidative stress in atherogenesis. The mechanisms of Nox5 regulation are not entirely elucidated. The aim of this study was t...
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| description | Histone acetylation plays a major role in epigenetic regulation of gene expression. Monocyte-derived macrophages express functional NADPH oxidase 5 (Nox5) that contributes to oxidative stress in atherogenesis. The mechanisms of Nox5 regulation are not entirely elucidated. The aim of this study was to investigate the expression pattern of key histone acetyltransferase subtypes (p300, HAT1) in human atherosclerosis and to determine their role in mediating the upregulation of Nox5 in macrophages under inflammatory conditions. Human nonatherosclerotic and atherosclerotic tissue samples were collected in order to determine the expression of p300 and HAT1 isoforms, H3K27ac, and Nox5. In vitro determinations were done on human macrophages exposed to lipopolysaccharide in the absence or presence of histone acetyltransferase inhibitors. Western blot, immunohistochemistry, immunofluorescence, real-time PCR, transfection, and chromatin immunoprecipitation assay were employed. The protein levels of p300 and HAT1 isoforms, H3K27ac, and Nox5 were found significantly elevated in human atherosclerotic specimens. Immunohistochemistry/immunofluorescence staining revealed that p300, HAT1, H3K27ac, H3K9ac, and Nox5 proteins were colocalized in the area of CD45+/CD68+ immune cells and lipid-rich deposits within human atherosclerotic plaques. Lipopolysaccharide induced the levels of HAT1, H3K27ac, H3K9ac, and Nox5 and the recruitment of p300 and HAT1 at the sites of active transcription within Nox5 gene promoter in cultured human macrophages. Pharmacological inhibition of histone acetyltransferase significantly reduced the Nox5 gene and protein expression in lipopolysaccharide-challenged macrophages. The overexpression of p300 or HAT1 enhanced the Nox5 gene promoter activity. The histone acetyltransferase system is altered in human atherosclerosis. Under inflammatory conditions, HAT subtypes control Nox5 overexpression in cultured human macrophages. The data suggest the existence of a new epigenetic mechanism underlying oxidative stress in atherosclerosis. |
| doi_str_mv | 10.1155/2019/3201062 |
| format | Article |
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Monocyte-derived macrophages express functional NADPH oxidase 5 (Nox5) that contributes to oxidative stress in atherogenesis. The mechanisms of Nox5 regulation are not entirely elucidated. The aim of this study was to investigate the expression pattern of key histone acetyltransferase subtypes (p300, HAT1) in human atherosclerosis and to determine their role in mediating the upregulation of Nox5 in macrophages under inflammatory conditions. Human nonatherosclerotic and atherosclerotic tissue samples were collected in order to determine the expression of p300 and HAT1 isoforms, H3K27ac, and Nox5. In vitro determinations were done on human macrophages exposed to lipopolysaccharide in the absence or presence of histone acetyltransferase inhibitors. Western blot, immunohistochemistry, immunofluorescence, real-time PCR, transfection, and chromatin immunoprecipitation assay were employed. The protein levels of p300 and HAT1 isoforms, H3K27ac, and Nox5 were found significantly elevated in human atherosclerotic specimens. Immunohistochemistry/immunofluorescence staining revealed that p300, HAT1, H3K27ac, H3K9ac, and Nox5 proteins were colocalized in the area of CD45+/CD68+ immune cells and lipid-rich deposits within human atherosclerotic plaques. Lipopolysaccharide induced the levels of HAT1, H3K27ac, H3K9ac, and Nox5 and the recruitment of p300 and HAT1 at the sites of active transcription within Nox5 gene promoter in cultured human macrophages. Pharmacological inhibition of histone acetyltransferase significantly reduced the Nox5 gene and protein expression in lipopolysaccharide-challenged macrophages. The overexpression of p300 or HAT1 enhanced the Nox5 gene promoter activity. The histone acetyltransferase system is altered in human atherosclerosis. Under inflammatory conditions, HAT subtypes control Nox5 overexpression in cultured human macrophages. The data suggest the existence of a new epigenetic mechanism underlying oxidative stress in atherosclerosis.</description><identifier>ISSN: 1942-0900</identifier><identifier>EISSN: 1942-0994</identifier><identifier>DOI: 10.1155/2019/3201062</identifier><identifier>PMID: 31565149</identifier><language>eng</language><publisher>Cairo, Egypt: Hindawi Publishing Corporation</publisher><subject>Atherosclerosis ; Atherosclerosis - enzymology ; Atherosclerosis - genetics ; Atherosclerosis - metabolism ; Atherosclerosis - pathology ; Cell culture ; Diabetes ; E1A-Associated p300 Protein - genetics ; E1A-Associated p300 Protein - metabolism ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Gene expression ; Genes ; Genetic transcription ; Histone Acetyltransferases - genetics ; Histone Acetyltransferases - metabolism ; Histones ; Histones - biosynthesis ; Histones - genetics ; Histones - metabolism ; Humans ; Immunohistochemistry ; Kinases ; Laboratories ; Lipopolysaccharides - pharmacology ; Macrophages ; Macrophages - drug effects ; Macrophages - enzymology ; Macrophages - pathology ; Mitogens ; NADPH Oxidase 5 - biosynthesis ; NADPH Oxidase 5 - genetics ; NADPH Oxidase 5 - metabolism ; Oxidases ; Oxidative stress ; Proteins ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Scientific equipment and supplies industry ; THP-1 Cells ; Transcription factors ; Transfection ; Up-Regulation</subject><ispartof>Oxidative medicine and cellular longevity, 2019, Vol.2019 (2019), p.1-17</ispartof><rights>Copyright © 2019 Mihaela-Loredana Vlad et al.</rights><rights>COPYRIGHT 2019 John Wiley & Sons, Inc.</rights><rights>Copyright © 2019 Mihaela-Loredana Vlad et al. This is an open access article distributed under the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. http://creativecommons.org/licenses/by/4.0</rights><rights>Copyright © 2019 Mihaela-Loredana Vlad et al. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c499t-841fa1d4607f488df2581bf55149558ecbeb4cf1d9977ca0c148ee8fabeb7e63</citedby><cites>FETCH-LOGICAL-c499t-841fa1d4607f488df2581bf55149558ecbeb4cf1d9977ca0c148ee8fabeb7e63</cites><orcidid>0000-0002-8795-3095</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745143/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745143/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,4024,27923,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31565149$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Moreno, Maria U.</contributor><contributor>Maria U Moreno</contributor><creatorcontrib>Manea, Adrian</creatorcontrib><creatorcontrib>Muresian, Horia</creatorcontrib><creatorcontrib>Raicu, Monica</creatorcontrib><creatorcontrib>Lazar, Alexandra-Gela</creatorcontrib><creatorcontrib>Manea, Simona-Adriana</creatorcontrib><creatorcontrib>Vlad, Mihaela-Loredana</creatorcontrib><creatorcontrib>Simionescu, Maya</creatorcontrib><title>Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis</title><title>Oxidative medicine and cellular longevity</title><addtitle>Oxid Med Cell Longev</addtitle><description>Histone acetylation plays a major role in epigenetic regulation of gene expression. Monocyte-derived macrophages express functional NADPH oxidase 5 (Nox5) that contributes to oxidative stress in atherogenesis. The mechanisms of Nox5 regulation are not entirely elucidated. The aim of this study was to investigate the expression pattern of key histone acetyltransferase subtypes (p300, HAT1) in human atherosclerosis and to determine their role in mediating the upregulation of Nox5 in macrophages under inflammatory conditions. Human nonatherosclerotic and atherosclerotic tissue samples were collected in order to determine the expression of p300 and HAT1 isoforms, H3K27ac, and Nox5. In vitro determinations were done on human macrophages exposed to lipopolysaccharide in the absence or presence of histone acetyltransferase inhibitors. Western blot, immunohistochemistry, immunofluorescence, real-time PCR, transfection, and chromatin immunoprecipitation assay were employed. The protein levels of p300 and HAT1 isoforms, H3K27ac, and Nox5 were found significantly elevated in human atherosclerotic specimens. Immunohistochemistry/immunofluorescence staining revealed that p300, HAT1, H3K27ac, H3K9ac, and Nox5 proteins were colocalized in the area of CD45+/CD68+ immune cells and lipid-rich deposits within human atherosclerotic plaques. Lipopolysaccharide induced the levels of HAT1, H3K27ac, H3K9ac, and Nox5 and the recruitment of p300 and HAT1 at the sites of active transcription within Nox5 gene promoter in cultured human macrophages. Pharmacological inhibition of histone acetyltransferase significantly reduced the Nox5 gene and protein expression in lipopolysaccharide-challenged macrophages. The overexpression of p300 or HAT1 enhanced the Nox5 gene promoter activity. The histone acetyltransferase system is altered in human atherosclerosis. Under inflammatory conditions, HAT subtypes control Nox5 overexpression in cultured human macrophages. The data suggest the existence of a new epigenetic mechanism underlying oxidative stress in atherosclerosis.</description><subject>Atherosclerosis</subject><subject>Atherosclerosis - enzymology</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - metabolism</subject><subject>Atherosclerosis - pathology</subject><subject>Cell culture</subject><subject>Diabetes</subject><subject>E1A-Associated p300 Protein - genetics</subject><subject>E1A-Associated p300 Protein - metabolism</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genetic transcription</subject><subject>Histone Acetyltransferases - genetics</subject><subject>Histone Acetyltransferases - metabolism</subject><subject>Histones</subject><subject>Histones - biosynthesis</subject><subject>Histones - genetics</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Macrophages</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - enzymology</subject><subject>Macrophages - pathology</subject><subject>Mitogens</subject><subject>NADPH Oxidase 5 - biosynthesis</subject><subject>NADPH Oxidase 5 - genetics</subject><subject>NADPH Oxidase 5 - metabolism</subject><subject>Oxidases</subject><subject>Oxidative stress</subject><subject>Proteins</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Scientific equipment and supplies industry</subject><subject>THP-1 Cells</subject><subject>Transcription factors</subject><subject>Transfection</subject><subject>Up-Regulation</subject><issn>1942-0900</issn><issn>1942-0994</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkk9v0zAYhyMEYmNw44wscUGCMjtx_u2AFHVAJ210gnGO3jqvG0-JHWyno5-VL4NDSwecuNiR_eT5-bXfKHrO6FvG0vQ0pqw8TcJIs_hBdMxKHs9oWfKHh29Kj6Inzt1SmiUxZ4-jo4SlWcp4eRz9WCjnjUZSCfTbzlvQTqIFh7NzHFA3qD25Bt_ewdaRK2wUeCRfB4vrsQOvjCZGkk_V-fWCLL-rJvxIUqI0WYw9aHIFwpqhhTU6MgaZJRdadtD34I3dkrnRjZok7oxU5Nr4kKagCzmiBa1cP8k_IwivNhj82zVq8mVAoYJvuUE7WNOM4tcxQmblW7TGiW4alXsaPZLQOXy2n0-imw_vb-aL2eXy48W8upwJXpZ-VnAmgTU8o7nkRdHIOC3YSqbTBaVpgWKFKy4ka8oyzwVQwXiBWEgI6zlmyUn0bqcdxlWPjQg1WOjqwaoe7LY2oOq_d7Rq67XZ1FnOQ0YSBK_2Amu-jeh83SsnsOtAoxldHcfhOXmZsyKgL_9Bb81odahuomiepklK76k1dFgrLU3IFZO0rjIaYsuMTbFvdlR4IucsysORGa2n1qqn1qr3rRXwF3-WeYB_91IAXu-AVukG7tR_6jAwKOGejmnCkiz5CdjQ5SI</recordid><startdate>2019</startdate><enddate>2019</enddate><creator>Manea, Adrian</creator><creator>Muresian, Horia</creator><creator>Raicu, Monica</creator><creator>Lazar, Alexandra-Gela</creator><creator>Manea, Simona-Adriana</creator><creator>Vlad, Mihaela-Loredana</creator><creator>Simionescu, Maya</creator><general>Hindawi Publishing Corporation</general><general>Hindawi</general><general>John Wiley & Sons, Inc</general><general>Hindawi Limited</general><scope>ADJCN</scope><scope>AHFXO</scope><scope>RHU</scope><scope>RHW</scope><scope>RHX</scope><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8795-3095</orcidid></search><sort><creationdate>2019</creationdate><title>Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis</title><author>Manea, Adrian ; Muresian, Horia ; Raicu, Monica ; Lazar, Alexandra-Gela ; Manea, Simona-Adriana ; Vlad, Mihaela-Loredana ; Simionescu, Maya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-841fa1d4607f488df2581bf55149558ecbeb4cf1d9977ca0c148ee8fabeb7e63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Atherosclerosis</topic><topic>Atherosclerosis - enzymology</topic><topic>Atherosclerosis - genetics</topic><topic>Atherosclerosis - metabolism</topic><topic>Atherosclerosis - pathology</topic><topic>Cell culture</topic><topic>Diabetes</topic><topic>E1A-Associated p300 Protein - genetics</topic><topic>E1A-Associated p300 Protein - metabolism</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetic inheritance</topic><topic>Epigenetics</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Genetic transcription</topic><topic>Histone Acetyltransferases - genetics</topic><topic>Histone Acetyltransferases - metabolism</topic><topic>Histones</topic><topic>Histones - biosynthesis</topic><topic>Histones - genetics</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Macrophages</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - enzymology</topic><topic>Macrophages - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oxidative medicine and cellular longevity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Manea, Adrian</au><au>Muresian, Horia</au><au>Raicu, Monica</au><au>Lazar, Alexandra-Gela</au><au>Manea, Simona-Adriana</au><au>Vlad, Mihaela-Loredana</au><au>Simionescu, Maya</au><au>Moreno, Maria U.</au><au>Maria U Moreno</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis</atitle><jtitle>Oxidative medicine and cellular longevity</jtitle><addtitle>Oxid Med Cell Longev</addtitle><date>2019</date><risdate>2019</risdate><volume>2019</volume><issue>2019</issue><spage>1</spage><epage>17</epage><pages>1-17</pages><issn>1942-0900</issn><eissn>1942-0994</eissn><abstract>Histone acetylation plays a major role in epigenetic regulation of gene expression. Monocyte-derived macrophages express functional NADPH oxidase 5 (Nox5) that contributes to oxidative stress in atherogenesis. The mechanisms of Nox5 regulation are not entirely elucidated. The aim of this study was to investigate the expression pattern of key histone acetyltransferase subtypes (p300, HAT1) in human atherosclerosis and to determine their role in mediating the upregulation of Nox5 in macrophages under inflammatory conditions. Human nonatherosclerotic and atherosclerotic tissue samples were collected in order to determine the expression of p300 and HAT1 isoforms, H3K27ac, and Nox5. In vitro determinations were done on human macrophages exposed to lipopolysaccharide in the absence or presence of histone acetyltransferase inhibitors. Western blot, immunohistochemistry, immunofluorescence, real-time PCR, transfection, and chromatin immunoprecipitation assay were employed. The protein levels of p300 and HAT1 isoforms, H3K27ac, and Nox5 were found significantly elevated in human atherosclerotic specimens. Immunohistochemistry/immunofluorescence staining revealed that p300, HAT1, H3K27ac, H3K9ac, and Nox5 proteins were colocalized in the area of CD45+/CD68+ immune cells and lipid-rich deposits within human atherosclerotic plaques. Lipopolysaccharide induced the levels of HAT1, H3K27ac, H3K9ac, and Nox5 and the recruitment of p300 and HAT1 at the sites of active transcription within Nox5 gene promoter in cultured human macrophages. Pharmacological inhibition of histone acetyltransferase significantly reduced the Nox5 gene and protein expression in lipopolysaccharide-challenged macrophages. The overexpression of p300 or HAT1 enhanced the Nox5 gene promoter activity. The histone acetyltransferase system is altered in human atherosclerosis. Under inflammatory conditions, HAT subtypes control Nox5 overexpression in cultured human macrophages. The data suggest the existence of a new epigenetic mechanism underlying oxidative stress in atherosclerosis.</abstract><cop>Cairo, Egypt</cop><pub>Hindawi Publishing Corporation</pub><pmid>31565149</pmid><doi>10.1155/2019/3201062</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-8795-3095</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1942-0900 |
| ispartof | Oxidative medicine and cellular longevity, 2019, Vol.2019 (2019), p.1-17 |
| issn | 1942-0900 1942-0994 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6745143 |
| source | MEDLINE; PubMed Central Open Access; Wiley Online Library Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Atherosclerosis Atherosclerosis - enzymology Atherosclerosis - genetics Atherosclerosis - metabolism Atherosclerosis - pathology Cell culture Diabetes E1A-Associated p300 Protein - genetics E1A-Associated p300 Protein - metabolism Epigenesis, Genetic Epigenetic inheritance Epigenetics Gene expression Genes Genetic transcription Histone Acetyltransferases - genetics Histone Acetyltransferases - metabolism Histones Histones - biosynthesis Histones - genetics Histones - metabolism Humans Immunohistochemistry Kinases Laboratories Lipopolysaccharides - pharmacology Macrophages Macrophages - drug effects Macrophages - enzymology Macrophages - pathology Mitogens NADPH Oxidase 5 - biosynthesis NADPH Oxidase 5 - genetics NADPH Oxidase 5 - metabolism Oxidases Oxidative stress Proteins Reactive oxygen species Reactive Oxygen Species - metabolism Scientific equipment and supplies industry THP-1 Cells Transcription factors Transfection Up-Regulation |
| title | Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T22%3A56%3A50IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Histone%20Acetyltransferase-Dependent%20Pathways%20Mediate%20Upregulation%20of%20NADPH%20Oxidase%205%20in%20Human%20Macrophages%20under%20Inflammatory%20Conditions:%20A%20Potential%20Mechanism%20of%20Reactive%20Oxygen%20Species%20Overproduction%20in%20Atherosclerosis&rft.jtitle=Oxidative%20medicine%20and%20cellular%20longevity&rft.au=Manea,%20Adrian&rft.date=2019&rft.volume=2019&rft.issue=2019&rft.spage=1&rft.epage=17&rft.pages=1-17&rft.issn=1942-0900&rft.eissn=1942-0994&rft_id=info:doi/10.1155/2019/3201062&rft_dat=%3Cgale_pubme%3EA606749613%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2290755350&rft_id=info:pmid/31565149&rft_galeid=A606749613&rfr_iscdi=true |