Serum metabolomics indicate altered cellular energy metabolism in children with cystic fibrosis

Joseloff, Elizabeth; Wang, Sha; Bell, Sara C.; Wetmore, Diana; Lawton, Kay A.; Milburn, Michael V.; Ryals, John; Guo, Lining; Muhlebach, Marianne S.

doi:10.1002/ppul.22859

Cited by 40 publications

(51 citation statements)

References 52 publications

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“…Importantly, the ratio of GSH / GSSG was significantly diminished in CF cells, strongly suggesting the presence of oxidative stress. Interestingly, metabolomic analysis of non-fasted CF patients revealed a decrease in β-oxidation of fatty acids, a marker of mitochondrial dysfunction (104), but did not detect significant differences in markers of oxidative stress in the blood between CF and non-CF cohorts. Similarly, lipidomic analyses of CF patient plasma (105,106) failed to detect differences in prostanes, lipids that are classically associated with CF plasma oxidative stress (24).…”

Section: Omics-based Studiesmentioning

confidence: 99%

Redox balance in Cystic Fibrosis

Ziady

Hansen

2014

The International Journal of Biochemistry & Cell Biology

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The homeostatic balance between oxidants and antioxidants in biological systems is known as redox balance, and is regulated by complex processes. Redox balance regulates many of the known cellular pathways and disease processes. The dysregulation of redox balance can lead to acute or long-term oxidative or reductive stresses that are associated with many of the abnormalities observed in cystic fibrosis (CF). Over the past 5 decades researchers have examined contributors to redox dysregulation, their molecular products, and their impact on ion transport, cell proliferation, inflammation, bacterial killing, and the metabolism of nucleic acids, proteins, and lipids in CF. CF patients exhibit elevated markers of oxidative stress when compared to non-CF healthy controls; however, whether the reported redox imbalance is sufficient to produce pathology has been controversial. In addition, comparisons between CF and non-CF disease controls have been lacking. To better understand the mechanisms which mediate the generation of oxidants and antioxidants in CF and the importance of their balance in effecting oxidative or reductive stress, we will review the determinants of redox balance in the blood, lumen, and cellular compartments. From the perspective of methodological application, we will focus on the approaches most often used to study oxidant and antioxidants in CF, including biochemical, proteomic, metabolomic, and lipidomic studies, with a discussion of the few transcriptomic analyses that predict changes in the expression of regulators of redox. Finally, we will discuss the utility of oxidants and antioxidants as biomarkers of disease and the use of antioxidant therapy in CF.

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Section: Omics-based Studiesmentioning

confidence: 99%

Redox balance in Cystic Fibrosis

Ziady

Hansen

2014

The International Journal of Biochemistry & Cell Biology

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“…MS can precisely and rapidly examine markers of disease or response to therapy broadly, allowing for global analyses of individual samples in a non-biased, data-driven approach. Metabolomic analyses of non-fasted CF patients revealed a decrease in β-oxidation of fatty acids, which is a marker of mitochondrial dysfunction (110), and CF plasma lipidomic studies have detected significant decreases in anti-inflammatory lipids (111). In CF sputum, a metabolomic/lipidomic analysis by Yang and colleagues identified a number of proinflammatory lipids (oxylipins) previously not identified in the CF lung (112).…”

Section: New Technologies and Toolsmentioning

confidence: 99%

Biomarkers for cystic fibrosis drug development

Muhlebach

Clancy

Heltshe

et al. 2016

Journal of Cystic Fibrosis

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Purpose To provide a review of the status of biomarkers in cystic fibrosis drug development, including regulatory definitions and considerations, a summary of biomarkers in current use with supportive data, current gaps, and future needs. Methods Biomarkers are considered across several areas of CF drug development, including cystic fibrosis transmembrane conductance regulator modulation, infection, and inflammation. Results Sweat chloride, nasal potential difference, and intestinal current measurements have been standardized and examined in the context of multicenter trials to quantify CFTR function. Detection and quantification of pathogenic bacteria in CF respiratory cultures (e.g.: Pseudomonas aeruginosa) is commonly used in early phase antimicrobial clinical trials, and to monitor safety of therapeutic interventions. Sputum (e.g.: neutrophil elastase, myeloperoxidase, calprotectin) and blood biomarkers (e.g.: C reactive protein, calprotectin, serum amyloid A) have had variable success in detecting response to inflammatory treatments. Conclusions Biomarkers are used throughout the drug development process in CF, and many have been used in early phase clinical trials to provide proof of concept, detect drug bioactivity, and inform dosing for later-phase studies. Advances in the precision of current biomarkers, and the identification of new biomarkers with ‘omics-based technologies, are needed to accelerate CF drug development.

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“…Mitochondrial biogenreduced airway responsiveness and a lung pathology that worsens over time, thus highlighting the potential importance of COX4i2 in the pathogenesis of asthma (7). Loss of the complex I OXPHOS proteins CISD1 and MT-ND4 (32), decreased complex I activity (33), and decreased FA oxidation (34) are also associated with CF, a lethal autosomal recessive disease associated with abnormal transport of chloride and sodium ions across the epithelium, leading to viscous airway secretions (Table 1).…”

Section: Bioenergetics and Nutrient Sensingmentioning

confidence: 99%