Cystic Fibrosis – a Multiorgan Protein Misfolding Disease

Fraser-Pitt, D.; O’Neil, Deborah A.

doi:10.4155/fso.15.57

Cited by 29 publications

(35 citation statements)

References 49 publications

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“…Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to misfolding of the CFTR protein and damage to the lung among other organs [ [275] , [276] , [277] ]. The misfolding of CFTR leads to increased ROS, reduced autophagy, accumulation of misfolded proteins in the airway epithelia of CF patients and inflammation [ 160 , 278 ] ( Fig.…”

Section: Autophagy and Ros In Pulmonary Diseasesmentioning

confidence: 99%

Complex interplay between autophagy and oxidative stress in the development of pulmonary disease

et al. 2020

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The autophagic pathway involves the encapsulation of substrates in double-membraned vesicles, which are subsequently delivered to the lysosome for enzymatic degradation and recycling of metabolic precursors. Autophagy is a major cellular defense against oxidative stress, or related conditions that cause accumulation of damaged proteins or organelles. Selective forms of autophagy can maintain organelle populations or remove aggregated proteins. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of reactive oxygen species (ROS), leading to oxidative stress and the associated oxidative damage of cellular components. Accumulating evidence indicates that autophagy is necessary to maintain redox homeostasis. ROS activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular damaged macromolecules and dysfunctional organelles. The cellular responses triggered by oxidative stress include the altered regulation of signaling pathways that culminate in the regulation of autophagy. Current research suggests a central role for autophagy as a mammalian oxidative stress response and its interrelationship to other stress defense systems. Altered autophagy phenotypes have been observed in lung diseases such as chronic obstructive lung disease, acute lung injury, cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension, and asthma. Understanding the mechanisms by which ROS regulate autophagy will provide novel therapeutic targets for lung diseases. This review highlights our current understanding on the interplay between ROS and autophagy in the development of pulmonary disease.

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Section: Autophagy and Ros In Pulmonary Diseasesmentioning

confidence: 99%

Complex interplay between autophagy and oxidative stress in the development of pulmonary disease

et al. 2020

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“…Individuals with CF are homozygous for CFTR alleles that negatively affect the transport, processing, or function of this ion channel. The most common of these alleles is the ∆F508 mutation [47]. Experiments using epithelial cell lines carrying either the wildtype or ∆F508 variants of CFTR indicated that the internalization of P. aeruginosa was reduced when mutant but not wildtype CFTR was expressed, suggesting that CFTR mutations may promote P. aeruginosa infection [44].…”

Section: Animal and Plant Receptors Recognize Lps And Mount An Immunementioning

confidence: 99%

The Role of Pseudomonas aeruginosa Lipopolysaccharide in Bacterial Pathogenesis and Physiology

2019

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The major constituent of the outer membrane of Gram-negative bacteria is lipopolysaccharide (LPS), which is comprised of lipid A, core oligosaccharide, and O antigen, which is a long polysaccharide chain extending into the extracellular environment. Due to the localization of LPS, it is a key molecule on the bacterial cell wall that is recognized by the host to deploy an immune defence in order to neutralize invading pathogens. However, LPS also promotes bacterial survival in a host environment by protecting the bacteria from these threats. This review explores the relationship between the different LPS glycoforms of the opportunistic pathogen Pseudomonas aeruginosa and the ability of this organism to cause persistent infections, especially in the genetic disease cystic fibrosis. We also discuss the role of LPS in facilitating biofilm formation, antibiotic resistance, and how LPS may be targeted by new antimicrobial therapies.

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“…Cystic fibrosis (CF) is an autosomal recessive inherited disease that leads to multi-system organ dysfunction, mainly affecting respiratory, digestive and reproductive systems [46][47][48].…”

Section: Iminosugars In Cystic Fibrosismentioning

confidence: 99%

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

Esposito

D’Alonzo

Fenza

et al. 2020

IJMS

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Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.

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Cystic Fibrosis – a Multiorgan Protein Misfolding Disease

Cited by 29 publications

References 49 publications

Complex interplay between autophagy and oxidative stress in the development of pulmonary disease

Complex interplay between autophagy and oxidative stress in the development of pulmonary disease

The Role of Pseudomonas aeruginosa Lipopolysaccharide in Bacterial Pathogenesis and Physiology

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

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