{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:37:00Z","timestamp":1790422620440,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2016,12,28]],"date-time":"2016-12-28T00:00:00Z","timestamp":1482883200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001655","name":"Deutscher Akademischer Austauschdienst","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Experimental Dermatology"],"published-print":{"date-parts":[[2017,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although there is increasing evidence that oxidative stress is involved in collagen synthesis and myofibroblast activation, the <jats:styled-content style=\"fixed-case\">NADPH<\/jats:styled-content> oxidase (Nox) system is incompletely investigated in the context of human dermal fibroblasts (<jats:styled-content style=\"fixed-case\">HDF<\/jats:styled-content>s) and skin fibrosis. Using the pan\u2010Nox inhibitor diphenyleneiodonium (<jats:styled-content style=\"fixed-case\">DPI<\/jats:styled-content>) as an initial tool, we show that gene expression of collagen type I, \u03b1\u2010smooth muscle actin (\u03b1\u2010<jats:styled-content style=\"fixed-case\">SMA<\/jats:styled-content>) and fibronectin 1 is suppressed in <jats:styled-content style=\"fixed-case\">HDF<\/jats:styled-content>s. Detailed expression analysis of all Nox isoforms and adaptors revealed expression of <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> and protein expression of Nox4, p22<jats:sup><jats:italic>phox<\/jats:italic><\/jats:sup> and Poldip2 but neither Nox1 nor Nox2. Nox4 could be immunolocalized to the endoplasmic reticulum. Importantly, <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010\u03b2<jats:sub>1<\/jats:sub> had a dose\u2010 and time\u2010dependent upregulating effect on <jats:styled-content style=\"fixed-case\">NADH<\/jats:styled-content> activity and Nox4 gene expression in <jats:styled-content style=\"fixed-case\">HDF<\/jats:styled-content>s. Genetic silencing of Nox4 as demonstrated by si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> in <jats:styled-content style=\"fixed-case\">HDF<\/jats:styled-content>s as well as in murine fibroblasts established from Nox4 knockout mice confirmed that <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010\u03b2<jats:sub>1<\/jats:sub>\u2010mediated collagen type I gene, \u03b1\u2010<jats:styled-content style=\"fixed-case\">SMA<\/jats:styled-content> and fibronectin 1 gene expressions were Nox4\u2010dependent. This <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010\u03b2<jats:sub>1<\/jats:sub> effect was mediated by Smad3 as shown by in silico promoter analysis, pharmacological inhibition and gene silencing of Smad3. The relevance of these findings is highlighted in the bleomycin\u2010induced scleroderma mouse model. <jats:styled-content style=\"fixed-case\">DPI<\/jats:styled-content> treatment attenuated skin fibrosis and myofibroblast activation. Moreover, Nox4 knockdown by si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> reduced skin collagen synthesis, \u03b1\u2010<jats:styled-content style=\"fixed-case\">SMA<\/jats:styled-content> and fibronectin 1 expression in vivo. Finally, analyses of <jats:styled-content style=\"fixed-case\">HDF<\/jats:styled-content>s from patients with systemic sclerosis confirmed the expression of Nox4 and its adaptors, whereas Nox1 and Nox2 were not detectable. Our findings indicate that Nox4 targeting is a promising future treatment for fibrotic skin diseases.<\/jats:p>","DOI":"10.1111\/exd.13180","type":"journal-article","created":{"date-parts":[[2016,8,30]],"date-time":"2016-08-30T13:38:35Z","timestamp":1472564315000},"page":"73-81","source":"Crossref","is-referenced-by-count":35,"title":["Targeting of <scp>NADPH<\/scp> oxidase in vitro and in vivo suppresses fibroblast activation and experimental skin fibrosis"],"prefix":"10.1111","volume":"26","author":[{"given":"Heba","family":"Dosoki","sequence":"first","affiliation":[{"name":"Department of Dermatology University of M\u00fcnster  M\u00fcnster Germany"},{"name":"Department of Botany and Microbiology Alexandria University  Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agatha","family":"Stegemann","sequence":"additional","affiliation":[{"name":"Department of Dermatology University of M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muna","family":"Taha","sequence":"additional","affiliation":[{"name":"Institute of Anatomy &amp; Vascular Biology University of M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Schnittler","sequence":"additional","affiliation":[{"name":"Institute of Anatomy &amp; Vascular Biology University of M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Luger","sequence":"additional","affiliation":[{"name":"Department of Dermatology University of M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Schr\u00f6der","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Physiology Goethe\u2010University  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg H. W.","family":"Distler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3 and Institute for Clinical Immunology University of Erlangen\u2010Nuremberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus","family":"Kerkhoff","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences School of Human Sciences University of Osnabr\u00fcck  Osnabr\u00fcck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"Department of Dermatology University of M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,12,28]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0190-9622(93)70014-K"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00044.2005"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.002980"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-012-1010-9"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403046200"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.130135897"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2005"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009020146"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406486200"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.084939"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2005.03.023"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.192138"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/exd.12497"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.37809"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.267054"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M702175200"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.1999.00528.x"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201746"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39084"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2443.2005.00907.x"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.10.3.12207"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.301787"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2011.09.030"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200111)44:11<2653::AID-ART445>3.0.CO;2-1"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20130091"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39242"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25938"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00396.2014"}],"container-title":["Experimental Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fexd.13180","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fexd.13180","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/exd.13180","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T10:51:12Z","timestamp":1695552672000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/exd.13180"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,28]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2017,1]]}},"alternative-id":["10.1111\/exd.13180"],"URL":"https:\/\/doi.org\/10.1111\/exd.13180","archive":["Portico"],"relation":{},"ISSN":["0906-6705","1600-0625"],"issn-type":[{"value":"0906-6705","type":"print"},{"value":"1600-0625","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,28]]}}}