Iguratimod inhibits skin fibrosis by regulating TGF‐β1/Smad signalling pathway in systemic sclerosis
Background Iguratimod (T‐614), exerting a powerful anti‐inflammatory ability, has therapeutic efficacy in multiple autoimmune diseases. However, the effect of T‐614 on systemic sclerosis (SSc) is unclear. Here, we investigate the effect and molecular mechanism of T‐614 in experimental SSc models. Me...
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| Veröffentlicht in: | European journal of clinical investigation 2022-08, Vol.52 (8), p.e13791-n/a |
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| creator | Xie, Xi Gan, Haina Tian, Jing li, Fen Chen, Jinwei Wang, Jia Liao, Jiafeng Li, Shu |
| description | Background
Iguratimod (T‐614), exerting a powerful anti‐inflammatory ability, has therapeutic efficacy in multiple autoimmune diseases. However, the effect of T‐614 on systemic sclerosis (SSc) is unclear. Here, we investigate the effect and molecular mechanism of T‐614 in experimental SSc models.
Methods
In vitro, cultured dermal fibroblasts from four SSc patients were subjected to different doses of T‐614 in the presence or absence of TGF‐β1 stimulation. Cell proliferation, apoptosis and migration were determined by CCK‐8, flow cytometry and transwell assay, respectively. Fibrosis markers and smad signalling pathway‐related proteins were detected by immunoblotting and immunofluorescence. In vivo, a bleomycin‐induced SSc mouse model was used to evaluate the effect of T‐614 on skin fibrosis. Pathological changes in skin tissues were evaluated by HE, Masson staining and immunohistochemistry.
Results
In the study, we found T‐614 inhibited TGF‐β1‐induced cell proliferation, migration and promoted apoptosis in a dose‐dependent manner (all p |
| doi_str_mv | 10.1111/eci.13791 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2652863552</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2688008060</sourcerecordid><originalsourceid>FETCH-LOGICAL-c2681-d2fa7cc7441b90cc75ba8785113389cca0eb300322d1e145f37295cf33807fdf3</originalsourceid><addsrcrecordid>eNp1kD1OwzAYQC0EouVn4ALIEgsMaf1TJ86IqrZUqsRAmSPHcVIXJylxoiobR-AsHIRDcBLcpjAg4cWWvqcnfw-AK4wG2J2hknqAaRDiI9DH1GceoT45Bn2E8MgjYUB64MzaNUKIY0pOQY-y0QgHiPdBNs-aStQ6LxOoi5WOdW2hfdEFTHVclVZbGLewUlljHFVkcDmbfr29f37g4VMuEmh1VghjdpONqFdb0ToNtK2tVa4ltNKoveUCnKTCWHV5uM_B83SyHD94i8fZfHy_8CTxOfYSkopAysB9Lw6Re7BY8IAzjCnloZQCqZgiRAlJsMIjltKAhEymboqCNEnpObjtvJuqfG2UraNcW6mMEYUqGxsRnxHuU8aIQ2_-oOuyqdw2O4pzFwv5yFF3HSXdHrZSabSpdC6qNsIo2tWPXP1oX9-x1wdjE-cq-SV_cjtg2AFbbVT7vymajOed8huFXY-b</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2688008060</pqid></control><display><type>article</type><title>Iguratimod inhibits skin fibrosis by regulating TGF‐β1/Smad signalling pathway in systemic sclerosis</title><source>Wiley Online Library Journals Frontfile Complete</source><creator>Xie, Xi ; Gan, Haina ; Tian, Jing ; li, Fen ; Chen, Jinwei ; Wang, Jia ; Liao, Jiafeng ; Li, Shu</creator><creatorcontrib>Xie, Xi ; Gan, Haina ; Tian, Jing ; li, Fen ; Chen, Jinwei ; Wang, Jia ; Liao, Jiafeng ; Li, Shu</creatorcontrib><description>Background
Iguratimod (T‐614), exerting a powerful anti‐inflammatory ability, has therapeutic efficacy in multiple autoimmune diseases. However, the effect of T‐614 on systemic sclerosis (SSc) is unclear. Here, we investigate the effect and molecular mechanism of T‐614 in experimental SSc models.
Methods
In vitro, cultured dermal fibroblasts from four SSc patients were subjected to different doses of T‐614 in the presence or absence of TGF‐β1 stimulation. Cell proliferation, apoptosis and migration were determined by CCK‐8, flow cytometry and transwell assay, respectively. Fibrosis markers and smad signalling pathway‐related proteins were detected by immunoblotting and immunofluorescence. In vivo, a bleomycin‐induced SSc mouse model was used to evaluate the effect of T‐614 on skin fibrosis. Pathological changes in skin tissues were evaluated by HE, Masson staining and immunohistochemistry.
Results
In the study, we found T‐614 inhibited TGF‐β1‐induced cell proliferation, migration and promoted apoptosis in a dose‐dependent manner (all p < 0.01). T‐614 partially reversed TGF‐β1‐induced upregulation of fibrosis markers and phosphorylation of smad2 and smad3 and blocked p‐Smad3 nuclear translocation (all p < 0.05), suggesting T‐614 may inhibit dermal fibroblasts activation by regulating TGF‐β1/smad pathway. In vivo experiments, T‐614 alleviated skin thickness in bleomycin‐induced SSc mice (all p < 0.05). The expression of fibrosis markers and the infiltration of macrophages in skin tissue were significantly decreased after T‐614 treatment (all p < 0.05).
Conclusion
Our preliminary data indicated T‐614 inhibited dermal fibroblasts activation and skin fibrosis at least partly by regulating TGF‐β1/smad pathway in experimental SSc models and may be a promising therapeutic agent for SSc.</description><identifier>ISSN: 0014-2972</identifier><identifier>EISSN: 1365-2362</identifier><identifier>DOI: 10.1111/eci.13791</identifier><identifier>PMID: 35441708</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Animal models ; Apoptosis ; Autoimmune diseases ; Bleomycin ; Cell growth ; Cell proliferation ; Chemical compounds ; Cholecystokinin ; Fibroblasts ; Fibrosis ; Flow cytometry ; iguratimod ; Immunoblotting ; Immunofluorescence ; Immunohistochemistry ; In vitro methods and tests ; Inflammation ; Leukocyte migration ; Macrophages ; Markers ; Molecular modelling ; Nuclear transport ; Pharmacology ; Phosphorylation ; Scleroderma ; Signal transduction ; Signaling ; Skin ; skin fibrosis ; Smad protein ; Smad2 protein ; Smad3 ; Smad3 protein ; Systemic sclerosis ; TGF‐β ; Translocation</subject><ispartof>European journal of clinical investigation, 2022-08, Vol.52 (8), p.e13791-n/a</ispartof><rights>2022 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.</rights><rights>Copyright © 2022 Stichting European Society for Clinical Investigation Journal Foundation</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2681-d2fa7cc7441b90cc75ba8785113389cca0eb300322d1e145f37295cf33807fdf3</citedby><cites>FETCH-LOGICAL-c2681-d2fa7cc7441b90cc75ba8785113389cca0eb300322d1e145f37295cf33807fdf3</cites><orcidid>0000-0002-9296-2324 ; 0000-0003-2740-6863</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Feci.13791$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Feci.13791$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35441708$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xie, Xi</creatorcontrib><creatorcontrib>Gan, Haina</creatorcontrib><creatorcontrib>Tian, Jing</creatorcontrib><creatorcontrib>li, Fen</creatorcontrib><creatorcontrib>Chen, Jinwei</creatorcontrib><creatorcontrib>Wang, Jia</creatorcontrib><creatorcontrib>Liao, Jiafeng</creatorcontrib><creatorcontrib>Li, Shu</creatorcontrib><title>Iguratimod inhibits skin fibrosis by regulating TGF‐β1/Smad signalling pathway in systemic sclerosis</title><title>European journal of clinical investigation</title><addtitle>Eur J Clin Invest</addtitle><description>Background
Iguratimod (T‐614), exerting a powerful anti‐inflammatory ability, has therapeutic efficacy in multiple autoimmune diseases. However, the effect of T‐614 on systemic sclerosis (SSc) is unclear. Here, we investigate the effect and molecular mechanism of T‐614 in experimental SSc models.
Methods
In vitro, cultured dermal fibroblasts from four SSc patients were subjected to different doses of T‐614 in the presence or absence of TGF‐β1 stimulation. Cell proliferation, apoptosis and migration were determined by CCK‐8, flow cytometry and transwell assay, respectively. Fibrosis markers and smad signalling pathway‐related proteins were detected by immunoblotting and immunofluorescence. In vivo, a bleomycin‐induced SSc mouse model was used to evaluate the effect of T‐614 on skin fibrosis. Pathological changes in skin tissues were evaluated by HE, Masson staining and immunohistochemistry.
Results
In the study, we found T‐614 inhibited TGF‐β1‐induced cell proliferation, migration and promoted apoptosis in a dose‐dependent manner (all p < 0.01). T‐614 partially reversed TGF‐β1‐induced upregulation of fibrosis markers and phosphorylation of smad2 and smad3 and blocked p‐Smad3 nuclear translocation (all p < 0.05), suggesting T‐614 may inhibit dermal fibroblasts activation by regulating TGF‐β1/smad pathway. In vivo experiments, T‐614 alleviated skin thickness in bleomycin‐induced SSc mice (all p < 0.05). The expression of fibrosis markers and the infiltration of macrophages in skin tissue were significantly decreased after T‐614 treatment (all p < 0.05).
Conclusion
Our preliminary data indicated T‐614 inhibited dermal fibroblasts activation and skin fibrosis at least partly by regulating TGF‐β1/smad pathway in experimental SSc models and may be a promising therapeutic agent for SSc.</description><subject>Animal models</subject><subject>Apoptosis</subject><subject>Autoimmune diseases</subject><subject>Bleomycin</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Chemical compounds</subject><subject>Cholecystokinin</subject><subject>Fibroblasts</subject><subject>Fibrosis</subject><subject>Flow cytometry</subject><subject>iguratimod</subject><subject>Immunoblotting</subject><subject>Immunofluorescence</subject><subject>Immunohistochemistry</subject><subject>In vitro methods and tests</subject><subject>Inflammation</subject><subject>Leukocyte migration</subject><subject>Macrophages</subject><subject>Markers</subject><subject>Molecular modelling</subject><subject>Nuclear transport</subject><subject>Pharmacology</subject><subject>Phosphorylation</subject><subject>Scleroderma</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Skin</subject><subject>skin fibrosis</subject><subject>Smad protein</subject><subject>Smad2 protein</subject><subject>Smad3</subject><subject>Smad3 protein</subject><subject>Systemic sclerosis</subject><subject>TGF‐β</subject><subject>Translocation</subject><issn>0014-2972</issn><issn>1365-2362</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp1kD1OwzAYQC0EouVn4ALIEgsMaf1TJ86IqrZUqsRAmSPHcVIXJylxoiobR-AsHIRDcBLcpjAg4cWWvqcnfw-AK4wG2J2hknqAaRDiI9DH1GceoT45Bn2E8MgjYUB64MzaNUKIY0pOQY-y0QgHiPdBNs-aStQ6LxOoi5WOdW2hfdEFTHVclVZbGLewUlljHFVkcDmbfr29f37g4VMuEmh1VghjdpONqFdb0ToNtK2tVa4ltNKoveUCnKTCWHV5uM_B83SyHD94i8fZfHy_8CTxOfYSkopAysB9Lw6Re7BY8IAzjCnloZQCqZgiRAlJsMIjltKAhEymboqCNEnpObjtvJuqfG2UraNcW6mMEYUqGxsRnxHuU8aIQ2_-oOuyqdw2O4pzFwv5yFF3HSXdHrZSabSpdC6qNsIo2tWPXP1oX9-x1wdjE-cq-SV_cjtg2AFbbVT7vymajOed8huFXY-b</recordid><startdate>202208</startdate><enddate>202208</enddate><creator>Xie, Xi</creator><creator>Gan, Haina</creator><creator>Tian, Jing</creator><creator>li, Fen</creator><creator>Chen, Jinwei</creator><creator>Wang, Jia</creator><creator>Liao, Jiafeng</creator><creator>Li, Shu</creator><general>Blackwell Publishing Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-9296-2324</orcidid><orcidid>https://orcid.org/0000-0003-2740-6863</orcidid></search><sort><creationdate>202208</creationdate><title>Iguratimod inhibits skin fibrosis by regulating TGF‐β1/Smad signalling pathway in systemic sclerosis</title><author>Xie, Xi ; Gan, Haina ; Tian, Jing ; li, Fen ; Chen, Jinwei ; Wang, Jia ; Liao, Jiafeng ; Li, Shu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2681-d2fa7cc7441b90cc75ba8785113389cca0eb300322d1e145f37295cf33807fdf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animal models</topic><topic>Apoptosis</topic><topic>Autoimmune diseases</topic><topic>Bleomycin</topic><topic>Cell growth</topic><topic>Cell proliferation</topic><topic>Chemical compounds</topic><topic>Cholecystokinin</topic><topic>Fibroblasts</topic><topic>Fibrosis</topic><topic>Flow cytometry</topic><topic>iguratimod</topic><topic>Immunoblotting</topic><topic>Immunofluorescence</topic><topic>Immunohistochemistry</topic><topic>In vitro methods and tests</topic><topic>Inflammation</topic><topic>Leukocyte migration</topic><topic>Macrophages</topic><topic>Markers</topic><topic>Molecular modelling</topic><topic>Nuclear transport</topic><topic>Pharmacology</topic><topic>Phosphorylation</topic><topic>Scleroderma</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Skin</topic><topic>skin fibrosis</topic><topic>Smad protein</topic><topic>Smad2 protein</topic><topic>Smad3</topic><topic>Smad3 protein</topic><topic>Systemic sclerosis</topic><topic>TGF‐β</topic><topic>Translocation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xie, Xi</creatorcontrib><creatorcontrib>Gan, Haina</creatorcontrib><creatorcontrib>Tian, Jing</creatorcontrib><creatorcontrib>li, Fen</creatorcontrib><creatorcontrib>Chen, Jinwei</creatorcontrib><creatorcontrib>Wang, Jia</creatorcontrib><creatorcontrib>Liao, Jiafeng</creatorcontrib><creatorcontrib>Li, Shu</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xie, Xi</au><au>Gan, Haina</au><au>Tian, Jing</au><au>li, Fen</au><au>Chen, Jinwei</au><au>Wang, Jia</au><au>Liao, Jiafeng</au><au>Li, Shu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Iguratimod inhibits skin fibrosis by regulating TGF‐β1/Smad signalling pathway in systemic sclerosis</atitle><jtitle>European journal of clinical investigation</jtitle><addtitle>Eur J Clin Invest</addtitle><date>2022-08</date><risdate>2022</risdate><volume>52</volume><issue>8</issue><spage>e13791</spage><epage>n/a</epage><pages>e13791-n/a</pages><issn>0014-2972</issn><eissn>1365-2362</eissn><abstract>Background
Iguratimod (T‐614), exerting a powerful anti‐inflammatory ability, has therapeutic efficacy in multiple autoimmune diseases. However, the effect of T‐614 on systemic sclerosis (SSc) is unclear. Here, we investigate the effect and molecular mechanism of T‐614 in experimental SSc models.
Methods
In vitro, cultured dermal fibroblasts from four SSc patients were subjected to different doses of T‐614 in the presence or absence of TGF‐β1 stimulation. Cell proliferation, apoptosis and migration were determined by CCK‐8, flow cytometry and transwell assay, respectively. Fibrosis markers and smad signalling pathway‐related proteins were detected by immunoblotting and immunofluorescence. In vivo, a bleomycin‐induced SSc mouse model was used to evaluate the effect of T‐614 on skin fibrosis. Pathological changes in skin tissues were evaluated by HE, Masson staining and immunohistochemistry.
Results
In the study, we found T‐614 inhibited TGF‐β1‐induced cell proliferation, migration and promoted apoptosis in a dose‐dependent manner (all p < 0.01). T‐614 partially reversed TGF‐β1‐induced upregulation of fibrosis markers and phosphorylation of smad2 and smad3 and blocked p‐Smad3 nuclear translocation (all p < 0.05), suggesting T‐614 may inhibit dermal fibroblasts activation by regulating TGF‐β1/smad pathway. In vivo experiments, T‐614 alleviated skin thickness in bleomycin‐induced SSc mice (all p < 0.05). The expression of fibrosis markers and the infiltration of macrophages in skin tissue were significantly decreased after T‐614 treatment (all p < 0.05).
Conclusion
Our preliminary data indicated T‐614 inhibited dermal fibroblasts activation and skin fibrosis at least partly by regulating TGF‐β1/smad pathway in experimental SSc models and may be a promising therapeutic agent for SSc.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>35441708</pmid><doi>10.1111/eci.13791</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-9296-2324</orcidid><orcidid>https://orcid.org/0000-0003-2740-6863</orcidid></addata></record> |
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| subjects | Animal models Apoptosis Autoimmune diseases Bleomycin Cell growth Cell proliferation Chemical compounds Cholecystokinin Fibroblasts Fibrosis Flow cytometry iguratimod Immunoblotting Immunofluorescence Immunohistochemistry In vitro methods and tests Inflammation Leukocyte migration Macrophages Markers Molecular modelling Nuclear transport Pharmacology Phosphorylation Scleroderma Signal transduction Signaling Skin skin fibrosis Smad protein Smad2 protein Smad3 Smad3 protein Systemic sclerosis TGF‐β Translocation |
| title | Iguratimod inhibits skin fibrosis by regulating TGF‐β1/Smad signalling pathway in systemic sclerosis |
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