Binding with HSP90β, cimifugin ameliorates fibrotic cataracts in vitro and in vivo by inhibiting TGFβ signaling pathways
Fibrotic cataracts, the most frequent complications after phacoemulsification, cannot be cured by drugs in clinic. The primary mechanism underlying the disease is the epithelial-mesenchymal transition (EMT). Cimifugin is a natural monomer component of traditional Chinese medicines. Previous research...
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Veröffentlicht in: | Experimental eye research 2024-12, Vol.249, p.110127, Article 110127 |
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creator | Ding, Xuefei Liu, Zhaochuan Li, Hailong Yue, Peilin Jia, Yuxuan Li, Enjie Lv, Ningxin Chen, Ting Fang, Rui Zhou, Honggang Song, Xudong |
description | Fibrotic cataracts, the most frequent complications after phacoemulsification, cannot be cured by drugs in clinic. The primary mechanism underlying the disease is the epithelial-mesenchymal transition (EMT). Cimifugin is a natural monomer component of traditional Chinese medicines. Previous researches have demonstrated the effect of cimifugin inhibiting EMT in the lung. The purpose of this work is to evaluate the impact of cimifugin on EMT in the lens and elucidate its precise mechanism. The pathogenesis of fibrotic cataracts was simulated using TGFβ2-induced cell model of EMT and the injury-induced anterior subcapsular cataract animal model. Through H&E staining and immunofluorescence of mice eyeballs, we discovered that cimifugin can inhibit the expansion of fibrotic lesions in vivo. Furthermore, at mRNA and protein levels, we confirmed that cimifugin can allay EMT of lens epithelial cells (LECs) in vitro and in vivo. Additionally, the inhibition of cimifugin on the activation of TGFβ-related signaling pathways was certified by immunoblot. HSP90β, the target of cimifugin, was predicted by network pharmacology and verified by drug affinity responsive target stability, the cellular thermal shift assay, and microscale thermophoresis. Moreover, co-immunoprecipitation revealed the interaction between HSP90β and TGFβ receptor (TGFβR) II. Together, our findings showed that by weakening the binding of HSP90β and TGFβRII, cimifugin suppressed the TGFβ signaling pathways to alleviate fibrotic cataracts. Cimifugin is a promising medication for the treatment of fibrotic cataracts.
[Display omitted]
•HSP90β is the target of cimifugin.•Binding with HSP90β, cimifugin can inhibit the activation of TGFβ-related signaling pathways.•By inhibition of TGFβ-related signaling pathways, cimifugin can alleviate EMT of lens epithelial cells. |
doi_str_mv | 10.1016/j.exer.2024.110127 |
format | Article |
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[Display omitted]
•HSP90β is the target of cimifugin.•Binding with HSP90β, cimifugin can inhibit the activation of TGFβ-related signaling pathways.•By inhibition of TGFβ-related signaling pathways, cimifugin can alleviate EMT of lens epithelial cells.</description><identifier>ISSN: 0014-4835</identifier><identifier>ISSN: 1096-0007</identifier><identifier>EISSN: 1096-0007</identifier><identifier>DOI: 10.1016/j.exer.2024.110127</identifier><identifier>PMID: 39424221</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Blotting, Western ; Cataract - drug therapy ; Cataract - metabolism ; Cataract - pathology ; Cells, Cultured ; Cimifugin ; Disease Models, Animal ; Epithelial Cells - drug effects ; Epithelial Cells - metabolism ; Epithelial-mesenchymal transition ; Epithelial-Mesenchymal Transition - drug effects ; Fibrosis ; HSP90 Heat-Shock Proteins - antagonists & inhibitors ; HSP90 Heat-Shock Proteins - metabolism ; HSP90β ; Lens, Crystalline - drug effects ; Lens, Crystalline - metabolism ; Lens, Crystalline - pathology ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, Transforming Growth Factor beta - antagonists & inhibitors ; Receptors, Transforming Growth Factor beta - metabolism ; Signal Transduction ; TGFβRII ; Transforming Growth Factor beta - metabolism</subject><ispartof>Experimental eye research, 2024-12, Vol.249, p.110127, Article 110127</ispartof><rights>2024 The Authors</rights><rights>Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c237t-7cb70e1592dec27c6dde4a79053db8cc12b653e150899f1dfa5fce8df23eef203</cites><orcidid>0000-0002-8036-5936</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.exer.2024.110127$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39424221$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ding, Xuefei</creatorcontrib><creatorcontrib>Liu, Zhaochuan</creatorcontrib><creatorcontrib>Li, Hailong</creatorcontrib><creatorcontrib>Yue, Peilin</creatorcontrib><creatorcontrib>Jia, Yuxuan</creatorcontrib><creatorcontrib>Li, Enjie</creatorcontrib><creatorcontrib>Lv, Ningxin</creatorcontrib><creatorcontrib>Chen, Ting</creatorcontrib><creatorcontrib>Fang, Rui</creatorcontrib><creatorcontrib>Zhou, Honggang</creatorcontrib><creatorcontrib>Song, Xudong</creatorcontrib><title>Binding with HSP90β, cimifugin ameliorates fibrotic cataracts in vitro and in vivo by inhibiting TGFβ signaling pathways</title><title>Experimental eye research</title><addtitle>Exp Eye Res</addtitle><description>Fibrotic cataracts, the most frequent complications after phacoemulsification, cannot be cured by drugs in clinic. The primary mechanism underlying the disease is the epithelial-mesenchymal transition (EMT). Cimifugin is a natural monomer component of traditional Chinese medicines. Previous researches have demonstrated the effect of cimifugin inhibiting EMT in the lung. The purpose of this work is to evaluate the impact of cimifugin on EMT in the lens and elucidate its precise mechanism. The pathogenesis of fibrotic cataracts was simulated using TGFβ2-induced cell model of EMT and the injury-induced anterior subcapsular cataract animal model. Through H&E staining and immunofluorescence of mice eyeballs, we discovered that cimifugin can inhibit the expansion of fibrotic lesions in vivo. Furthermore, at mRNA and protein levels, we confirmed that cimifugin can allay EMT of lens epithelial cells (LECs) in vitro and in vivo. Additionally, the inhibition of cimifugin on the activation of TGFβ-related signaling pathways was certified by immunoblot. HSP90β, the target of cimifugin, was predicted by network pharmacology and verified by drug affinity responsive target stability, the cellular thermal shift assay, and microscale thermophoresis. Moreover, co-immunoprecipitation revealed the interaction between HSP90β and TGFβ receptor (TGFβR) II. Together, our findings showed that by weakening the binding of HSP90β and TGFβRII, cimifugin suppressed the TGFβ signaling pathways to alleviate fibrotic cataracts. Cimifugin is a promising medication for the treatment of fibrotic cataracts.
[Display omitted]
•HSP90β is the target of cimifugin.•Binding with HSP90β, cimifugin can inhibit the activation of TGFβ-related signaling pathways.•By inhibition of TGFβ-related signaling pathways, cimifugin can alleviate EMT of lens epithelial cells.</description><subject>Animals</subject><subject>Blotting, Western</subject><subject>Cataract - drug therapy</subject><subject>Cataract - metabolism</subject><subject>Cataract - pathology</subject><subject>Cells, Cultured</subject><subject>Cimifugin</subject><subject>Disease Models, Animal</subject><subject>Epithelial Cells - drug effects</subject><subject>Epithelial Cells - metabolism</subject><subject>Epithelial-mesenchymal transition</subject><subject>Epithelial-Mesenchymal Transition - drug effects</subject><subject>Fibrosis</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>HSP90β</subject><subject>Lens, Crystalline - drug effects</subject><subject>Lens, Crystalline - metabolism</subject><subject>Lens, Crystalline - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Receptors, Transforming Growth Factor beta - antagonists & inhibitors</subject><subject>Receptors, Transforming Growth Factor beta - metabolism</subject><subject>Signal Transduction</subject><subject>TGFβRII</subject><subject>Transforming Growth Factor beta - metabolism</subject><issn>0014-4835</issn><issn>1096-0007</issn><issn>1096-0007</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtuEzEUhi0EoqH0BVggL1kwwbfJzEhsoKItUqVWol1bHvs4OdFcgu2khMfqg_SZ8GgKS1b2Ofr-XzofIe84W3LGV5-2S_gFYSmYUEueN6J6QRacNauCMVa9JAvGuCpULcsT8ibGbd5KVanX5EQ2Sigh-IL8_oqDw2FNHzBt6NWP24Y9PX6kFnv0-zUO1PTQ4RhMgkg9tmFMaKk1yQRjU6SZOGAKIzWDm4fDSNtj_m6wxTQ1311ePD3SiOvBdNO8M2nzYI7xLXnlTRfh7Pk9JfcX3-7Or4rrm8vv51-uCytklYrKthUDXjbCgRWVXTkHylQNK6Vra2u5aFelzACrm8Zz503pLdTOCwngBZOn5MPcuwvjzz3EpHuMFrrODDDuo5ac15IpVZcZFTNqwxhjAK93AXsTjpozPTnXWz0515NzPTvPoffP_fu2B_cv8ldyBj7PAOQrD5jj0SIMFhwGsEm7Ef_X_wfh_5Wr</recordid><startdate>202412</startdate><enddate>202412</enddate><creator>Ding, Xuefei</creator><creator>Liu, Zhaochuan</creator><creator>Li, Hailong</creator><creator>Yue, Peilin</creator><creator>Jia, Yuxuan</creator><creator>Li, Enjie</creator><creator>Lv, Ningxin</creator><creator>Chen, Ting</creator><creator>Fang, Rui</creator><creator>Zhou, Honggang</creator><creator>Song, Xudong</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><orcidid>https://orcid.org/0000-0002-8036-5936</orcidid></search><sort><creationdate>202412</creationdate><title>Binding with HSP90β, cimifugin ameliorates fibrotic cataracts in vitro and in vivo by inhibiting TGFβ signaling pathways</title><author>Ding, Xuefei ; Liu, Zhaochuan ; Li, Hailong ; Yue, Peilin ; Jia, Yuxuan ; Li, Enjie ; Lv, Ningxin ; Chen, Ting ; Fang, Rui ; Zhou, Honggang ; Song, Xudong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c237t-7cb70e1592dec27c6dde4a79053db8cc12b653e150899f1dfa5fce8df23eef203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Blotting, Western</topic><topic>Cataract - drug therapy</topic><topic>Cataract - metabolism</topic><topic>Cataract - pathology</topic><topic>Cells, Cultured</topic><topic>Cimifugin</topic><topic>Disease Models, Animal</topic><topic>Epithelial Cells - drug effects</topic><topic>Epithelial Cells - metabolism</topic><topic>Epithelial-mesenchymal transition</topic><topic>Epithelial-Mesenchymal Transition - drug effects</topic><topic>Fibrosis</topic><topic>HSP90 Heat-Shock Proteins - antagonists & inhibitors</topic><topic>HSP90 Heat-Shock Proteins - metabolism</topic><topic>HSP90β</topic><topic>Lens, Crystalline - drug effects</topic><topic>Lens, Crystalline - metabolism</topic><topic>Lens, Crystalline - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Receptors, Transforming Growth Factor beta - antagonists & inhibitors</topic><topic>Receptors, Transforming Growth Factor beta - metabolism</topic><topic>Signal Transduction</topic><topic>TGFβRII</topic><topic>Transforming Growth Factor beta - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ding, Xuefei</creatorcontrib><creatorcontrib>Liu, Zhaochuan</creatorcontrib><creatorcontrib>Li, Hailong</creatorcontrib><creatorcontrib>Yue, Peilin</creatorcontrib><creatorcontrib>Jia, Yuxuan</creatorcontrib><creatorcontrib>Li, Enjie</creatorcontrib><creatorcontrib>Lv, Ningxin</creatorcontrib><creatorcontrib>Chen, Ting</creatorcontrib><creatorcontrib>Fang, Rui</creatorcontrib><creatorcontrib>Zhou, Honggang</creatorcontrib><creatorcontrib>Song, Xudong</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental eye research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ding, Xuefei</au><au>Liu, Zhaochuan</au><au>Li, Hailong</au><au>Yue, Peilin</au><au>Jia, Yuxuan</au><au>Li, Enjie</au><au>Lv, Ningxin</au><au>Chen, Ting</au><au>Fang, Rui</au><au>Zhou, Honggang</au><au>Song, Xudong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Binding with HSP90β, cimifugin ameliorates fibrotic cataracts in vitro and in vivo by inhibiting TGFβ signaling pathways</atitle><jtitle>Experimental eye research</jtitle><addtitle>Exp Eye Res</addtitle><date>2024-12</date><risdate>2024</risdate><volume>249</volume><spage>110127</spage><pages>110127-</pages><artnum>110127</artnum><issn>0014-4835</issn><issn>1096-0007</issn><eissn>1096-0007</eissn><abstract>Fibrotic cataracts, the most frequent complications after phacoemulsification, cannot be cured by drugs in clinic. The primary mechanism underlying the disease is the epithelial-mesenchymal transition (EMT). Cimifugin is a natural monomer component of traditional Chinese medicines. Previous researches have demonstrated the effect of cimifugin inhibiting EMT in the lung. The purpose of this work is to evaluate the impact of cimifugin on EMT in the lens and elucidate its precise mechanism. The pathogenesis of fibrotic cataracts was simulated using TGFβ2-induced cell model of EMT and the injury-induced anterior subcapsular cataract animal model. Through H&E staining and immunofluorescence of mice eyeballs, we discovered that cimifugin can inhibit the expansion of fibrotic lesions in vivo. Furthermore, at mRNA and protein levels, we confirmed that cimifugin can allay EMT of lens epithelial cells (LECs) in vitro and in vivo. Additionally, the inhibition of cimifugin on the activation of TGFβ-related signaling pathways was certified by immunoblot. HSP90β, the target of cimifugin, was predicted by network pharmacology and verified by drug affinity responsive target stability, the cellular thermal shift assay, and microscale thermophoresis. Moreover, co-immunoprecipitation revealed the interaction between HSP90β and TGFβ receptor (TGFβR) II. Together, our findings showed that by weakening the binding of HSP90β and TGFβRII, cimifugin suppressed the TGFβ signaling pathways to alleviate fibrotic cataracts. Cimifugin is a promising medication for the treatment of fibrotic cataracts.
[Display omitted]
•HSP90β is the target of cimifugin.•Binding with HSP90β, cimifugin can inhibit the activation of TGFβ-related signaling pathways.•By inhibition of TGFβ-related signaling pathways, cimifugin can alleviate EMT of lens epithelial cells.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>39424221</pmid><doi>10.1016/j.exer.2024.110127</doi><orcidid>https://orcid.org/0000-0002-8036-5936</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Blotting, Western Cataract - drug therapy Cataract - metabolism Cataract - pathology Cells, Cultured Cimifugin Disease Models, Animal Epithelial Cells - drug effects Epithelial Cells - metabolism Epithelial-mesenchymal transition Epithelial-Mesenchymal Transition - drug effects Fibrosis HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - metabolism HSP90β Lens, Crystalline - drug effects Lens, Crystalline - metabolism Lens, Crystalline - pathology Male Mice Mice, Inbred C57BL Receptors, Transforming Growth Factor beta - antagonists & inhibitors Receptors, Transforming Growth Factor beta - metabolism Signal Transduction TGFβRII Transforming Growth Factor beta - metabolism |
title | Binding with HSP90β, cimifugin ameliorates fibrotic cataracts in vitro and in vivo by inhibiting TGFβ signaling pathways |
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