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Inhibitory effect of doxycycline conjugated with deoxycholic acid and polyethylenimine conjugate on nasal fibroblast differentiation and extracellular production.
- Source :
-
PloS one [PLoS One] 2024 May 16; Vol. 19 (5), pp. e0285655. Date of Electronic Publication: 2024 May 16 (Print Publication: 2024). - Publication Year :
- 2024
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Abstract
- Background: Chronic rhinosinusitis (CRS) is an inflammatory disease affecting the sinuses or nose. Persistent inflammatory responses can lead to tissue remodeling, which is a pathological characteristics of CRS. Activation of fibroblasts in the nasal mucosal stroma, differentiation and collagen deposition, and subepithelial fibrosis have been associated with CRS.<br />Objectives: We aimed to assess the inhibitory effects of doxycycline and deoxycholic acid-polyethyleneimine conjugate (DA3-Doxy) on myofibroblast differentiation and extracellular matrix (ECM) production in nasal fibroblasts stimulated with TGF-β1.<br />Methods: To enhance efficacy, we prepared DA3-Doxy using a conjugate of low-molecular-weight polyethyleneimine (PEI) (MW 1800) and deoxycholic acid (DA) and Doxy. The synthesis of the DA3-Doxy polymer was confirmed using nuclear magnetic resonance, and the critical micelle concentration required for cationic micelle formation through self-assembly was determined. Subsequently, the Doxy loading efficiency of DA3 was assessed. The cytotoxicity of Doxy, DA3, PEI, and DA-Doxy in nasal fibroblasts was evaluated using the WST-1 assay. The anti-tissue remodeling and anti-inflammatory effects of DA3-Doxy and DA3 were examined using real-time polymerase chain reaction (Real-time PCR), immunocytochemistry, western blot, and Sircol assay.<br />Results: Both DA3 and DA3-Doxy exhibited cytotoxicity at 10 μg/ml in nasal fibroblasts. Doxy partially inhibited α-smooth muscle actin, collagen types I and III, and fibronectin. However, DA3-Doxy significantly inhibited α-SMA, collagen types I and III, and fibronectin at 5 μg/ml. DA3-Doxy also modulated TGF-β1-induced changes in the expression of MMP 1, 2, and 9. Nonetheless, TGF-β1-induced expression of MMP3 was further increased by DA3-Doxy. The expression of TIMP 1 and 2 was partially reduced with 5 μg/ml DA3-Doxy.<br />Conclusions: Although initially developed for the delivery of genetic materials or drugs, DA3 exhibits inhibitory effects on myofibroblast differentiation and ECM production. Therefore, it holds therapeutic potential for CRS, and a synergistic effect can be expected when loaded with CRS treatment drugs.<br /> (Copyright: © 2024 Shin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Subjects :
- Humans
Extracellular Matrix metabolism
Extracellular Matrix drug effects
Transforming Growth Factor beta1 metabolism
Myofibroblasts drug effects
Myofibroblasts metabolism
Nasal Mucosa drug effects
Nasal Mucosa metabolism
Nasal Mucosa cytology
Actins metabolism
Polyethyleneimine chemistry
Polyethyleneimine pharmacology
Deoxycholic Acid chemistry
Deoxycholic Acid pharmacology
Fibroblasts drug effects
Fibroblasts metabolism
Cell Differentiation drug effects
Doxycycline pharmacology
Doxycycline chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 19
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 38753593
- Full Text :
- https://doi.org/10.1371/journal.pone.0285655