Condition : Cystic Fibrosis
Intervention : Dietary Supplement: Cystic Fibrosis Ready to Use Supplemental Food
Sponsors : Washington University School of Medicine; Cystic Fibrosis Foundation
Ready to Use Therapeutic Food (RUTF) to Promote Growth in Cystic Fibrosis
Mon, 12 Mar 2018 12:00:00 EDT
Last Update Posted: 03/26/19 09:41AM
In Vitro Activity of a Novel Glycopolymer against Biofilms of Burkholderia cepacia Complex Cystic Fibrosis Clinical Isolates.
Antimicrob Agents Chemother. 2019 Mar 25;:
Authors: Narayanaswamy VP, Duncan AP, LiPuma JJ, Wiesmann WP, Baker SM, Townsend SM
Burkholderia cepacia complex (Bcc) lung infections in cystic fibrosis (CF) patients are often associated with a steady decline in lung function and death. The formation of biofilms and inherent multi-drug resistance are virulence factors associated with Bcc infection and contribute to increased risk of mortality in CF patients. New therapeutic strategies targeting bacterial biofilms are anticipated to enhance antibiotic penetration and facilitate resolution of infection. Poly (acetyl, arginyl) glucosamine (PAAG), is a cationic glycopolymer therapeutic being developed to directly target biofilm integrity. In this study, thirteen isolates from 7 species were examined including; B. multivorans, B. cenocepacia, B. gladioli, B. dolosa, B. vietnamiensis, and B. cepacia These isolates were selected for their resistance to standard clinical antibiotics and their ability to form biofilms in vitro. Biofilm biomass was quantitated using static tissue culture plate (TCP) biofilm methods and minimum biofilm eradication concentration (MBEC) assay. Confocal laser scanning microscopy (CLSM) visualized biofilm removal by PAAG during treatment. Both TCP and MBEC methods demonstrated a significant dose-dependent relationship with regard to biofilm removal by 50-200μg/ml PAAG following 1-hour treatment (p<0.01). A significant reduction in biofilm thickness was observed following 10-minute treatment of Bcc biofilms with PAAG compared to vehicle control (p<0.001) in TCP, MBEC, and CLSM analysis. PAAG also rapidly permeabilizes bacteria within the first 10 minutes of treatment. Glycopolymers such as PAAG, are a new class of large-molecule therapeutics that support the treatment of recalcitrant Bcc biofilm. PMID: 30910901 [PubMed - as supplied by publisher] PubMed:30910901
Acetyl-CoA carboxylase inhibition regulates microtubule dynamics and intracellular transport in cystic fibrosis epithelial cells.
Am J Physiol Lung Cell Mol Physiol. 2019 Mar 20;:
Authors: Rymut SM, Lu B, Perez A, Corey DA, Lamb K, Cotton CU, Kelley TJ
The use of high-dose ibuprofen as an anti-inflammatory therapy in cystic fibrosis has been shown to be an effective intervention though use is limited due to potential adverse events. Identifying the mechanism of ibuprofen efficacy would aid in the development of new therapies that avoid these adverse events. Previous findings demonstrated that ibuprofen treatment restores the regulation of microtubule dynamics in cystic fibrosis (CF) epithelial cells through a 5′ adenosine monophosphate-activated protein kinase (AMPK)-dependent mechanism. The goal of this study is to define the AMPK pathway that leads to microtubule regulation. Here, it is identified that inhibition of acetyl-CoA carboxylase (ACC) is the key step in mediating the AMPK effect. ACC inhibition with 5-(Tetradecyloxy)-2-furoic acid (TOFA) increases microtubule reformation rates in cultured and primary CF epithelial cells to WT rates. TOFA treatment also restores microtubule dependent distribution of cholesterol and Rab7-positive organelles, as well as reduces expression of the pro-inflammatory signaling molecule RhoA to WT levels. ACC activation with citrate replicates these CF phenotypes in WT cells further supporting the role of AMPK signaling through ACC as a key mediator in CF cell signaling. It is concluded that ACC inhibition is the key step in the efficacy of AMPK activation at the cellular level and could represent a novel site of therapeutic intervention to address inflammation in CF.
PMID: 30892081 [PubMed – as supplied by publisher]
Aerosolized agents for airway clearance in cystic fibrosis.
Pediatr Pulmonol. 2019 Mar 18;:
Authors: Southern KW, Clancy JP, Ranganathan S
The outlook for people with cystic fibrosis (CF) has improved considerably as a result of conventional therapies including aerosolized agents for airway clearance. These will continue to play a significant role in maintaining well-being and improving survival, even as newer agents emerge that correct the underlying CF defect. In this review, we explore the evidence supporting the use of dornase alfa, hypertonic saline, and mannitol in improving mucus clearance in patients with CF from different age groups with differing disease severity. We also discuss the clinical use of these agents in the context of available international guidelines as well as practical considerations in the clinic, highlighting the importance of a multidisciplinary approach and shared decision-making. Unanswered questions regarding the optimal use of these agents are highlighted.
PMID: 30884217 [PubMed – as supplied by publisher]
Biochemistry of very-long-chain and long-chain ceramides in cystic fibrosis and other diseases: The importance of side chain.
Prog Lipid Res. 2019 Mar 12;:
Authors: Garić D, De Sanctis JB, Shah J, Dumut DC, Radzioch D
Ceramides, the principal building blocks of all sphingolipids, have attracted the attention of many scientists around the world interested in developing treatments for cystic fibrosis, the most common genetic disease of Caucasians. Many years of fruitful research in this field have produced some fundamentally important, yet controversial results. Here, we aimed to summarize the current knowledge on the role of long- and very-long- chain ceramides, the most abundant species of ceramides in animal cells, in cystic fibrosis and other diseases. We also aim to explain the importance of the length of their side chain in the context of stability of transmembrane proteins through a concise synthesis of their biophysical chemistry, cell biology, and physiology. This review also addresses several remaining riddles in this field. Finally, we discuss the technical challenges associated with the analysis and quantification of ceramides. We provide the evaluation of the antibodies used for ceramide quantification and we demonstrate their lack of specificity. Results and discussion presented here will be of interest to anyone studying these enigmatic lipids.
PMID: 30876862 [PubMed – as supplied by publisher]