Nrf2 antioxidant pathway suppresses Numb-mediated epithelial–mesenchymal transition during pulmonary fibrosis
Epithelial mesenchymal transition (EMT) is a key progression that promotes pulmonary fibrosis (PF). Numb, a phosphotyrosine-binding domain (PTB) protein, is implicated with EMT. Nuclear factor erythroid 2-related factor2 (Nrf2) and its downstream proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone...
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| Veröffentlicht in: | Cell death & disease 2018-01, Vol.9 (2), p.83-11, Article 83 |
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| description | Epithelial mesenchymal transition (EMT) is a key progression that promotes pulmonary fibrosis (PF). Numb, a phosphotyrosine-binding domain (PTB) protein, is implicated with EMT. Nuclear factor erythroid 2-related factor2 (Nrf2) and its downstream proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) constitute an important pathway of antioxidant defense signal for protecting against PF. It remains elusive whether Nrf2 antioxidant pathway and Numb have a potential relationship in EMT-mediated PF. Here, we observed the effects of Nrf2 pathway and Numb on bleomycin(BLM)-induced PF in Nrf2-knockout (Nrf2
−/−
) and wild-type (WT) mice. Meanwhile, rat type II alveolar epithelial cells line (RLE-6TN) and human epithelial cells line (A549) were both treated with an Nrf2 activator sulforaphane (SFN), or transfected siRNAs of Nrf2 and Numb to unravel roles of Nrf2 pathway, Numb and the link between them on transforming growth factor β1 (TGF-β1)-induced EMT. We found BLM-induced lung fibrosis were more severe in Nrf2
−/−
mice compared to WT mice with reduced expressions of HO-1 and NQO1. Numb was enhanced with down-regulated expressions of Nrf2 in BLM groups and further increased in Nrf2
−/−
groups. In vitro, given exogenous TGF-β1 on RLE-6TN and A549 up-regulated Numb expressions, accompanied with down-regulations of Nrf2 and its target proteins HO-1 and NQO1. Transfected with Nrf2 and Numb siRNAs further aggravated and relieved the progression of EMT, respectively. Inversely, activating Nrf2 pathway by SFN reduced the expression of Numb and EMT-related protein. Moreover, Numb deficiency by siRNA relieved the protection of activating Nrf2 against EMT. In conclusion, activating Nrf2 antioxidant pathway suppresses EMT during PF via inhibiting the abnormal expression of Numb. These findings provide insight into PF pathogenesis and a basis for novel treatment approaches. |
| doi_str_mv | 10.1038/s41419-017-0198-x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5833372</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1990474654</sourcerecordid><originalsourceid>FETCH-LOGICAL-c466t-42387f76f974ad8b2f3c2588207d78a76842e2cb554864a3ba197c0e76aa10373</originalsourceid><addsrcrecordid>eNp1UctOwzAQtBAIUOkHcEGWOAf8iu1ckBDiJVVwgbPlJE7rKnGCnUB74x_4Q74EVy1VOWDJ2pV2dnZ2B4BTjC4wovIyMMxwliAs4s9kstgDxwQxnDAps_2d_AiMQ5ij-ChFJOWH4IhklBNGyTFon3xFoHa9bRe2jBF2up996CUMQ9d5E4IJ8Glo8qQxpdW9KaHpbD8ztdX19-dXY4JxxWzZ6Br2XrtgI5OD5eCtm8JuqJvWab-Elc19G2w4AQeVroMZb-IIvN7dvtw8JJPn-8eb60lSMM77hBEqRSV4lQmmS5mTihYklZIgUQqpBZeMGFLkacokZ5rmGmeiQEZwreN1BB2BqzVvN-RReWFcVFerztsmylGttupvxdmZmrbvKpWUUkEiwfmGwLdvgwm9mreDd1GzwlmGmGA8ZRGF16gibhe8qbYTMFIrm9TaJhVtUiub1CL2nO1K23b8mhIBZA0I3eqKxu-M_pf1BwnsojA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1990474654</pqid></control><display><type>article</type><title>Nrf2 antioxidant pathway suppresses Numb-mediated epithelial–mesenchymal transition during pulmonary fibrosis</title><source>MEDLINE</source><source>Nature Free</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Springer Nature OA Free Journals</source><creator>Zhang, Zhihui ; Qu, Jiao ; Zheng, Cheng ; Zhang, Panpan ; Zhou, Wencheng ; Cui, Wenhui ; Mo, Xiaoting ; Li, Liucheng ; Xu, Liang ; Gao, Jian</creator><creatorcontrib>Zhang, Zhihui ; Qu, Jiao ; Zheng, Cheng ; Zhang, Panpan ; Zhou, Wencheng ; Cui, Wenhui ; Mo, Xiaoting ; Li, Liucheng ; Xu, Liang ; Gao, Jian</creatorcontrib><description>Epithelial mesenchymal transition (EMT) is a key progression that promotes pulmonary fibrosis (PF). Numb, a phosphotyrosine-binding domain (PTB) protein, is implicated with EMT. Nuclear factor erythroid 2-related factor2 (Nrf2) and its downstream proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) constitute an important pathway of antioxidant defense signal for protecting against PF. It remains elusive whether Nrf2 antioxidant pathway and Numb have a potential relationship in EMT-mediated PF. Here, we observed the effects of Nrf2 pathway and Numb on bleomycin(BLM)-induced PF in Nrf2-knockout (Nrf2
−/−
) and wild-type (WT) mice. Meanwhile, rat type II alveolar epithelial cells line (RLE-6TN) and human epithelial cells line (A549) were both treated with an Nrf2 activator sulforaphane (SFN), or transfected siRNAs of Nrf2 and Numb to unravel roles of Nrf2 pathway, Numb and the link between them on transforming growth factor β1 (TGF-β1)-induced EMT. We found BLM-induced lung fibrosis were more severe in Nrf2
−/−
mice compared to WT mice with reduced expressions of HO-1 and NQO1. Numb was enhanced with down-regulated expressions of Nrf2 in BLM groups and further increased in Nrf2
−/−
groups. In vitro, given exogenous TGF-β1 on RLE-6TN and A549 up-regulated Numb expressions, accompanied with down-regulations of Nrf2 and its target proteins HO-1 and NQO1. Transfected with Nrf2 and Numb siRNAs further aggravated and relieved the progression of EMT, respectively. Inversely, activating Nrf2 pathway by SFN reduced the expression of Numb and EMT-related protein. Moreover, Numb deficiency by siRNA relieved the protection of activating Nrf2 against EMT. In conclusion, activating Nrf2 antioxidant pathway suppresses EMT during PF via inhibiting the abnormal expression of Numb. These findings provide insight into PF pathogenesis and a basis for novel treatment approaches.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-017-0198-x</identifier><identifier>PMID: 29362432</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/89 ; Alveoli ; Animals ; Antibodies ; Antioxidants ; Antioxidants - metabolism ; Biochemistry ; Biomedical and Life Sciences ; Bleomycin ; Cell Biology ; Cell Culture ; Cell Line ; Disease Models, Animal ; Down-Regulation - drug effects ; Epithelial cells ; Epithelial-Mesenchymal Transition ; Fibrosis ; Gene Silencing - drug effects ; Heme ; Heme oxygenase (decyclizing) ; Humans ; Immunology ; Intracellular Signaling Peptides and Proteins - metabolism ; Isothiocyanates - pharmacology ; Life Sciences ; Lung diseases ; Membrane Proteins - metabolism ; Mesenchyme ; Mice, Knockout ; Models, Biological ; NAD ; Nerve Tissue Proteins - metabolism ; NF-E2-Related Factor 2 - metabolism ; NUMB protein ; Oxygenase ; Pathogenesis ; Phosphotyrosine ; Protein deficiency ; Pulmonary fibrosis ; Pulmonary Fibrosis - metabolism ; Pulmonary Fibrosis - pathology ; Quinone oxidoreductase ; Rats ; Rodents ; siRNA ; Sulforaphane ; Sulfoxides ; Transforming Growth Factor beta1 - pharmacology ; Transforming growth factor-b1</subject><ispartof>Cell death & disease, 2018-01, Vol.9 (2), p.83-11, Article 83</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c466t-42387f76f974ad8b2f3c2588207d78a76842e2cb554864a3ba197c0e76aa10373</citedby><cites>FETCH-LOGICAL-c466t-42387f76f974ad8b2f3c2588207d78a76842e2cb554864a3ba197c0e76aa10373</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833372/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833372/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29362432$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Zhihui</creatorcontrib><creatorcontrib>Qu, Jiao</creatorcontrib><creatorcontrib>Zheng, Cheng</creatorcontrib><creatorcontrib>Zhang, Panpan</creatorcontrib><creatorcontrib>Zhou, Wencheng</creatorcontrib><creatorcontrib>Cui, Wenhui</creatorcontrib><creatorcontrib>Mo, Xiaoting</creatorcontrib><creatorcontrib>Li, Liucheng</creatorcontrib><creatorcontrib>Xu, Liang</creatorcontrib><creatorcontrib>Gao, Jian</creatorcontrib><title>Nrf2 antioxidant pathway suppresses Numb-mediated epithelial–mesenchymal transition during pulmonary fibrosis</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Epithelial mesenchymal transition (EMT) is a key progression that promotes pulmonary fibrosis (PF). Numb, a phosphotyrosine-binding domain (PTB) protein, is implicated with EMT. Nuclear factor erythroid 2-related factor2 (Nrf2) and its downstream proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) constitute an important pathway of antioxidant defense signal for protecting against PF. It remains elusive whether Nrf2 antioxidant pathway and Numb have a potential relationship in EMT-mediated PF. Here, we observed the effects of Nrf2 pathway and Numb on bleomycin(BLM)-induced PF in Nrf2-knockout (Nrf2
−/−
) and wild-type (WT) mice. Meanwhile, rat type II alveolar epithelial cells line (RLE-6TN) and human epithelial cells line (A549) were both treated with an Nrf2 activator sulforaphane (SFN), or transfected siRNAs of Nrf2 and Numb to unravel roles of Nrf2 pathway, Numb and the link between them on transforming growth factor β1 (TGF-β1)-induced EMT. We found BLM-induced lung fibrosis were more severe in Nrf2
−/−
mice compared to WT mice with reduced expressions of HO-1 and NQO1. Numb was enhanced with down-regulated expressions of Nrf2 in BLM groups and further increased in Nrf2
−/−
groups. In vitro, given exogenous TGF-β1 on RLE-6TN and A549 up-regulated Numb expressions, accompanied with down-regulations of Nrf2 and its target proteins HO-1 and NQO1. Transfected with Nrf2 and Numb siRNAs further aggravated and relieved the progression of EMT, respectively. Inversely, activating Nrf2 pathway by SFN reduced the expression of Numb and EMT-related protein. Moreover, Numb deficiency by siRNA relieved the protection of activating Nrf2 against EMT. In conclusion, activating Nrf2 antioxidant pathway suppresses EMT during PF via inhibiting the abnormal expression of Numb. These findings provide insight into PF pathogenesis and a basis for novel treatment approaches.</description><subject>13/1</subject><subject>13/89</subject><subject>Alveoli</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antioxidants</subject><subject>Antioxidants - metabolism</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Bleomycin</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Line</subject><subject>Disease Models, Animal</subject><subject>Down-Regulation - drug effects</subject><subject>Epithelial cells</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Fibrosis</subject><subject>Gene Silencing - drug effects</subject><subject>Heme</subject><subject>Heme oxygenase (decyclizing)</subject><subject>Humans</subject><subject>Immunology</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Isothiocyanates - pharmacology</subject><subject>Life Sciences</subject><subject>Lung diseases</subject><subject>Membrane Proteins - metabolism</subject><subject>Mesenchyme</subject><subject>Mice, Knockout</subject><subject>Models, Biological</subject><subject>NAD</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>NUMB protein</subject><subject>Oxygenase</subject><subject>Pathogenesis</subject><subject>Phosphotyrosine</subject><subject>Protein deficiency</subject><subject>Pulmonary fibrosis</subject><subject>Pulmonary Fibrosis - metabolism</subject><subject>Pulmonary Fibrosis - pathology</subject><subject>Quinone oxidoreductase</subject><subject>Rats</subject><subject>Rodents</subject><subject>siRNA</subject><subject>Sulforaphane</subject><subject>Sulfoxides</subject><subject>Transforming Growth Factor beta1 - pharmacology</subject><subject>Transforming growth factor-b1</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1UctOwzAQtBAIUOkHcEGWOAf8iu1ckBDiJVVwgbPlJE7rKnGCnUB74x_4Q74EVy1VOWDJ2pV2dnZ2B4BTjC4wovIyMMxwliAs4s9kstgDxwQxnDAps_2d_AiMQ5ij-ChFJOWH4IhklBNGyTFon3xFoHa9bRe2jBF2up996CUMQ9d5E4IJ8Glo8qQxpdW9KaHpbD8ztdX19-dXY4JxxWzZ6Br2XrtgI5OD5eCtm8JuqJvWab-Elc19G2w4AQeVroMZb-IIvN7dvtw8JJPn-8eb60lSMM77hBEqRSV4lQmmS5mTihYklZIgUQqpBZeMGFLkacokZ5rmGmeiQEZwreN1BB2BqzVvN-RReWFcVFerztsmylGttupvxdmZmrbvKpWUUkEiwfmGwLdvgwm9mreDd1GzwlmGmGA8ZRGF16gibhe8qbYTMFIrm9TaJhVtUiub1CL2nO1K23b8mhIBZA0I3eqKxu-M_pf1BwnsojA</recordid><startdate>20180123</startdate><enddate>20180123</enddate><creator>Zhang, Zhihui</creator><creator>Qu, Jiao</creator><creator>Zheng, Cheng</creator><creator>Zhang, Panpan</creator><creator>Zhou, Wencheng</creator><creator>Cui, Wenhui</creator><creator>Mo, Xiaoting</creator><creator>Li, Liucheng</creator><creator>Xu, Liang</creator><creator>Gao, Jian</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><scope>C6C</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>88A</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope></search><sort><creationdate>20180123</creationdate><title>Nrf2 antioxidant pathway suppresses Numb-mediated epithelial–mesenchymal transition during pulmonary fibrosis</title><author>Zhang, Zhihui ; Qu, Jiao ; Zheng, Cheng ; Zhang, Panpan ; Zhou, Wencheng ; Cui, Wenhui ; Mo, Xiaoting ; Li, Liucheng ; Xu, Liang ; Gao, Jian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c466t-42387f76f974ad8b2f3c2588207d78a76842e2cb554864a3ba197c0e76aa10373</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>13/1</topic><topic>13/89</topic><topic>Alveoli</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antioxidants</topic><topic>Antioxidants - metabolism</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Bleomycin</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell Line</topic><topic>Disease Models, Animal</topic><topic>Down-Regulation - drug effects</topic><topic>Epithelial cells</topic><topic>Epithelial-Mesenchymal Transition</topic><topic>Fibrosis</topic><topic>Gene Silencing - drug effects</topic><topic>Heme</topic><topic>Heme oxygenase (decyclizing)</topic><topic>Humans</topic><topic>Immunology</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Isothiocyanates - pharmacology</topic><topic>Life Sciences</topic><topic>Lung diseases</topic><topic>Membrane Proteins - metabolism</topic><topic>Mesenchyme</topic><topic>Mice, Knockout</topic><topic>Models, Biological</topic><topic>NAD</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>NUMB protein</topic><topic>Oxygenase</topic><topic>Pathogenesis</topic><topic>Phosphotyrosine</topic><topic>Protein deficiency</topic><topic>Pulmonary fibrosis</topic><topic>Pulmonary Fibrosis - metabolism</topic><topic>Pulmonary Fibrosis - pathology</topic><topic>Quinone oxidoreductase</topic><topic>Rats</topic><topic>Rodents</topic><topic>siRNA</topic><topic>Sulforaphane</topic><topic>Sulfoxides</topic><topic>Transforming Growth Factor beta1 - pharmacology</topic><topic>Transforming growth factor-b1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Zhihui</creatorcontrib><creatorcontrib>Qu, Jiao</creatorcontrib><creatorcontrib>Zheng, Cheng</creatorcontrib><creatorcontrib>Zhang, Panpan</creatorcontrib><creatorcontrib>Zhou, Wencheng</creatorcontrib><creatorcontrib>Cui, Wenhui</creatorcontrib><creatorcontrib>Mo, Xiaoting</creatorcontrib><creatorcontrib>Li, Liucheng</creatorcontrib><creatorcontrib>Xu, Liang</creatorcontrib><creatorcontrib>Gao, Jian</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech 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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Zhihui</au><au>Qu, Jiao</au><au>Zheng, Cheng</au><au>Zhang, Panpan</au><au>Zhou, Wencheng</au><au>Cui, Wenhui</au><au>Mo, Xiaoting</au><au>Li, Liucheng</au><au>Xu, Liang</au><au>Gao, Jian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nrf2 antioxidant pathway suppresses Numb-mediated epithelial–mesenchymal transition during pulmonary fibrosis</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2018-01-23</date><risdate>2018</risdate><volume>9</volume><issue>2</issue><spage>83</spage><epage>11</epage><pages>83-11</pages><artnum>83</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Epithelial mesenchymal transition (EMT) is a key progression that promotes pulmonary fibrosis (PF). Numb, a phosphotyrosine-binding domain (PTB) protein, is implicated with EMT. Nuclear factor erythroid 2-related factor2 (Nrf2) and its downstream proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) constitute an important pathway of antioxidant defense signal for protecting against PF. It remains elusive whether Nrf2 antioxidant pathway and Numb have a potential relationship in EMT-mediated PF. Here, we observed the effects of Nrf2 pathway and Numb on bleomycin(BLM)-induced PF in Nrf2-knockout (Nrf2
−/−
) and wild-type (WT) mice. Meanwhile, rat type II alveolar epithelial cells line (RLE-6TN) and human epithelial cells line (A549) were both treated with an Nrf2 activator sulforaphane (SFN), or transfected siRNAs of Nrf2 and Numb to unravel roles of Nrf2 pathway, Numb and the link between them on transforming growth factor β1 (TGF-β1)-induced EMT. We found BLM-induced lung fibrosis were more severe in Nrf2
−/−
mice compared to WT mice with reduced expressions of HO-1 and NQO1. Numb was enhanced with down-regulated expressions of Nrf2 in BLM groups and further increased in Nrf2
−/−
groups. In vitro, given exogenous TGF-β1 on RLE-6TN and A549 up-regulated Numb expressions, accompanied with down-regulations of Nrf2 and its target proteins HO-1 and NQO1. Transfected with Nrf2 and Numb siRNAs further aggravated and relieved the progression of EMT, respectively. Inversely, activating Nrf2 pathway by SFN reduced the expression of Numb and EMT-related protein. Moreover, Numb deficiency by siRNA relieved the protection of activating Nrf2 against EMT. In conclusion, activating Nrf2 antioxidant pathway suppresses EMT during PF via inhibiting the abnormal expression of Numb. These findings provide insight into PF pathogenesis and a basis for novel treatment approaches.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29362432</pmid><doi>10.1038/s41419-017-0198-x</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13/1 13/89 Alveoli Animals Antibodies Antioxidants Antioxidants - metabolism Biochemistry Biomedical and Life Sciences Bleomycin Cell Biology Cell Culture Cell Line Disease Models, Animal Down-Regulation - drug effects Epithelial cells Epithelial-Mesenchymal Transition Fibrosis Gene Silencing - drug effects Heme Heme oxygenase (decyclizing) Humans Immunology Intracellular Signaling Peptides and Proteins - metabolism Isothiocyanates - pharmacology Life Sciences Lung diseases Membrane Proteins - metabolism Mesenchyme Mice, Knockout Models, Biological NAD Nerve Tissue Proteins - metabolism NF-E2-Related Factor 2 - metabolism NUMB protein Oxygenase Pathogenesis Phosphotyrosine Protein deficiency Pulmonary fibrosis Pulmonary Fibrosis - metabolism Pulmonary Fibrosis - pathology Quinone oxidoreductase Rats Rodents siRNA Sulforaphane Sulfoxides Transforming Growth Factor beta1 - pharmacology Transforming growth factor-b1 |
| title | Nrf2 antioxidant pathway suppresses Numb-mediated epithelial–mesenchymal transition during pulmonary fibrosis |
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