دورية أكاديمية
Inhibition of the rapamycin-insensitive mTORC1 /4E-BP1 axis attenuates TGF-β1-induced fibrotic response in human Tenon's fibroblasts.
| العنوان: | Inhibition of the rapamycin-insensitive mTORC1 /4E-BP1 axis attenuates TGF-β1-induced fibrotic response in human Tenon's fibroblasts. |
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| المؤلفون: | Zou J; The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China., Wu B; The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China., Tao Y; The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China., Liu Z; The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China., Zhao H; The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China., Wang P; The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China., Liang Y; The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China; National Clinical Research Center for Ocular Diseases, Wenzhou, China; Glaucoma Research Institute, Wenzhou Medical University, Wenzhou, China., Qu J; The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China; National Clinical Research Center for Ocular Diseases, Wenzhou, China. Electronic address: jia.qu@eye.ac.cn., Zhang S; The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China; National Clinical Research Center for Ocular Diseases, Wenzhou, China; Glaucoma Research Institute, Wenzhou Medical University, Wenzhou, China. Electronic address: shaodan_zhang@eye.ac.cn. |
| المصدر: | Experimental eye research [Exp Eye Res] 2024 Jul; Vol. 244, pp. 109927. Date of Electronic Publication: 2024 May 13. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Academic Press Country of Publication: England NLM ID: 0370707 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0007 (Electronic) Linking ISSN: 00144835 NLM ISO Abbreviation: Exp Eye Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: London : Academic Press Original Publication: London. |
| مواضيع طبية MeSH: | Transforming Growth Factor beta1*/metabolism , Mechanistic Target of Rapamycin Complex 1*/metabolism , Mechanistic Target of Rapamycin Complex 1*/antagonists & inhibitors , Fibroblasts*/metabolism , Fibroblasts*/drug effects , Fibroblasts*/pathology , Sirolimus*/pharmacology , Fibrosis*/metabolism , Tenon Capsule*/metabolism , Tenon Capsule*/drug effects , Adaptor Proteins, Signal Transducing*/metabolism , Adaptor Proteins, Signal Transducing*/genetics, Animals ; Humans ; Rats ; Cells, Cultured ; Cell Movement/drug effects ; Disease Models, Animal ; Blotting, Western ; Rats, Sprague-Dawley ; Cell Cycle Proteins/metabolism ; Signal Transduction ; Real-Time Polymerase Chain Reaction ; Male ; Glaucoma/metabolism ; Glaucoma/drug therapy ; Glaucoma/pathology ; Immunosuppressive Agents/pharmacology |
| مستخلص: | Subconjunctival fibrosis is the major cause of failure in both conventional and modern minimally invasive glaucoma surgeries (MIGSs) with subconjunctival filtration. The search for safe and effective anti-fibrotic agents is critical for improving long-term surgical outcomes. In this study, we investigated the effect of inhibiting the rapamycin-insensitive mTORC1/4E-BP1 axis on the transforming growth factor-beta 1(TGF-β1)-induced fibrotic responses in human Tenon's fibroblasts (HTFs), as well as in a rat model of glaucoma filtration surgery (GFS). Primary cultured HTFs were treated with 3 ng/mL TGF-β1 for 24 h, followed by treatment with 10 μM CZ415 for additional 24 h. Rapamycin (10 μM) was utilized as a control for mTORC1/4E-BP1 signaling insensitivity. The expression levels of fibrosis-associated molecules were measured using quantitative real-time PCR, Western blotting, and immunofluorescence analysis. Cell migration was assessed through the scratch wound assay. Additionally, a rat model of GFS was employed to evaluate the anti-fibrotic effect of CZ415 in vivo. Our findings indicated that both rapamycin and CZ415 treatment significantly reduced the TGF-β1-induced cell proliferation, migration, and the expression of pro-fibrotic factors in HTFs. CZ415 also more effectively inhibited TGF-β1-mediated collagen synthesis in HTFs compared to rapamycin. Activation of mTORC1/4E-BP signaling following TGF-β1 exposure was highly suppressed by CZ415 but was only modestly inhibited by rapamycin. Furthermore, CZ415 was found to decrease subconjunctival collagen deposition in rats post GFS. Our results suggest that rapamycin-insensitive mTORC1/4E-BP1 signaling plays a critical role in TGF-β Competing Interests: Declaration of competing interest No conflict of interest existed for all authors. (Copyright © 2024 Elsevier Ltd. All rights reserved.) |
| فهرسة مساهمة: | Keywords: CZ415; Collagen; Fibrosis; Glaucoma; mTORC1/4E-BP1 |
| المشرفين على المادة: | 0 (Transforming Growth Factor beta1) EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) W36ZG6FT64 (Sirolimus) 0 (EIF4EBP1 protein, human) 0 (Adaptor Proteins, Signal Transducing) 0 (Cell Cycle Proteins) 0 (Immunosuppressive Agents) |
| تواريخ الأحداث: | Date Created: 20240516 Date Completed: 20240614 Latest Revision: 20240627 |
| رمز التحديث: | 20240627 |
| DOI: | 10.1016/j.exer.2024.109927 |
| PMID: | 38750784 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1096-0007 |
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| DOI: | 10.1016/j.exer.2024.109927 |