ArticlePloS one2017
Dendrimer-based selective autophagy-induction rescues ΔF508-CFTR and inhibits Pseudomonas aeruginosa infection in cystic fibrosis.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 2 of them syntheses that pooled it.
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Who cites it
13 citing papers in PubMed, 2 syntheses or guidelines pooled it, 27 citations in OpenAlex.
- Meta-Analysis of Drug Delivery Approaches for Treating Intracellular Infections.Pharmaceutical research · 2022Pooled it
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- The Multifaceted Roles of Autophagy in Infectious, Obstructive, and Malignant Airway Diseases.Biomedicines · 2022Review
- Emerging Concepts in Defective Macrophage Phagocytosis in Cystic Fibrosis.International journal of molecular sciences · 2022Review
- Protein clearance strategies for disease intervention.Journal of neural transmission (Vienna, Austria : 1996) · 2022Review
- Bacterial Subversion of Autophagy in Cystic Fibrosis.Frontiers in cellular and infection microbiology · 2021Review
- Drug efficacy and toxicity prediction: an innovative application of transcriptomic data.Cell biology and toxicology · 2020Article
- Review
- Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies.Pharmaceutics · 2020Review
- Nanomedicine Approaches for the Pulmonary Treatment of Cystic Fibrosis.Frontiers in bioengineering and biotechnology · 2019Review
- Adapting Proteostasis and Autophagy for Controlling the Pathogenesis of Cystic Fibrosis Lung Disease.Frontiers in pharmacology · 2019Review
- l-Cysteine and l-Serine Modified Dendrimer with Multiple Reduced Thiols as a Kidney-Targeting Reactive Oxygen Species Scavenger to Prevent Renal Ischemia/Reperfusion Injury.Pharmaceutics · 2018Article
- Silencing of the Hsp70-specific nucleotide-exchange factor BAG3 corrects the F508del-CFTR variant by restoring autophagy.The Journal of biological chemistry · 2018Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCystic Fibrosis (CF) is a genetic disorder caused by mutation(s) in the CF-transmembrane conductance regulator (Cftr) gene. The most common mutation, ΔF508, leads to accumulation of defective-CFTR protein in aggresome-bodies. Additionally, Pseudomonas aeruginosa (Pa), a common CF pathogen, exacerbates obstructive CF lung pathology. In the present study, we aimed to develop and test a novel strategy to improve the bioavailability and potentially achieve targeted drug delivery of cysteamine, a potent autophagy-inducing drug with anti-bacterial properties, by developing a dendrimer (PAMAM-DEN)-based cysteamine analogue.
resultsWe first evaluated the effect of dendrimer-based cysteamine analogue (PAMAM-DENCYS) on the intrinsic autophagy response in IB3-1 cells and observed a significant reduction in Ub-RFP and LC3-GFP co-localization (aggresome-bodies) by PAMAM-DENCYS treatment as compared to plain dendrimer (PAMAM-DEN) control. Next, we observed that PAMAM-DENCYS treatment shows a modest rescue of ΔF508-CFTR as the C-form. Moreover, immunofluorescence microscopy of HEK-293 cells transfected with ΔF508-CFTR-GFP showed that PAMAM-DENCYS is able to rescue the misfolded-ΔF508-CFTR from aggresome-bodies by inducing its trafficking to the plasma membrane. We further verified these results by flow cytometry and observed significant (p<0.05; PAMAM-DEN vs. PAMAM-DENCYS) rescue of membrane-ΔF508-CFTR with PAMAM-DENCYS treatment using non-permeabilized IB3-1 cells immunostained for CFTR. Finally, we assessed the autophagy-mediated bacterial clearance potential of PAMAM-DENCYS by treating IB3-1 cells infected with PA01-GFP, and observed a significant (p<0.01; PAMAM-DEN vs. PAMAM-DENCYS) decrease in intracellular bacterial counts by immunofluorescence microscopy and flow cytometry. Also, PAMAM-DENCYS treatment significantly inhibits the growth of PA01-GFP bacteria and demonstrates potent mucolytic properties.
conclusionsWe demonstrate here the efficacy of dendrimer-based autophagy-induction in preventing sequestration of ΔF508-CFTR to aggresome-bodies while promoting its trafficking to the plasma membrane. Moreover, PAMAM-DENCYS decreases Pa infection and growth, while showing mucolytic properties, suggesting its potential in rescuing Pa-induced ΔF508-CF lung disease that warrants further investigation in CF murine model.
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