ArticleProceedings of the National Academy of Sciences of the United States of America2016
Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 63 citations in OpenAlex.
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- A potent endocytosis inhibitor Ikarugamycin up-regulates TNF production.Biochemistry and biophysics reports · 2021Article
- Integrative chemogenomic analysis identifies small molecules that partially rescue ΔF508-CFTR for cystic fibrosis.CPT: pharmacometrics & systems pharmacology · 2021Article
- Identification of 37 Heterogeneous Drug Candidates for Treatment of COVID-19 via a Rational Transcriptomics-Based Drug Repurposing Approach.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Quercetin Preserves Oral Cavity Health by Mitigating Inflammation and Microbial Dysbiosis.Frontiers in immunology · 2021Article
- The Advantages of Connectivity Map Applied in Traditional Chinese Medicine.Frontiers in pharmacology · 2021Review
- Role of Cystic Fibrosis Bronchial Epithelium in Neutrophil Chemotaxis.Frontiers in immunology · 2020Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections' map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o-, CFBE41o-) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells.
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