A novel guluronate oligomer improves intestinal transit and survival in cystic fibrosis mice

Vitko, Megan; Valerio, Dana M.; Rye, Phil D.; Onsøyen, E.; Myrset, Astrid Hilde; Dessen, A.; Drumm, Mitchell L.; Hodges, Craig A.

doi:10.1016/j.jcf.2016.06.005

Cited by 23 publications

(21 citation statements)

References 43 publications

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“…CF mice on a liquid diet [32, 33] or a solid diet with an osmotic laxative in the water [34] have a significant reduction in intestinal obstruction, but still display reduced growth. Similarly, treatment with a novel guluronate oligomer, OligoG, which reduces intestinal mucus accumulation, improved survival in CF mice, but did not restore normal growth [35]. In addition, genetic approaches to reduce intestinal obstruction in CF models have not resulted in a normal growth profile.…”

Section: Resultsmentioning

confidence: 99%

Growth deficits in cystic fibrosis mice begin in utero prior to IGF-1 reduction

et al. 2017

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Growth deficits are common in cystic fibrosis (CF), but their cause is complex, with contributions from exocrine pancreatic insufficiency, pulmonary complications, gastrointestinal obstructions, and endocrine abnormalities. The CF mouse model displays similar growth impairment despite exocrine pancreatic function and in the absence of chronic pulmonary infection. The high incidence of intestinal obstruction in the CF mouse has been suggested to significantly contribute to the observed growth deficits. Previous studies by our group have shown that restoration of the cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium prevents intestinal obstruction but does not improve growth. In this study, we further investigate growth deficits in CF and gut-corrected CF mice by assessing insulin-like growth factor 1 (IGF-1). IGF-1 levels were significantly decreased in CF and gut-corrected CF adult mice compared to wildtype littermates and were highly correlated with weight. Interestingly, perinatal IGF-1 levels were not significantly different between CF and wildtype littermates, even though growth deficits in CF mice could be detected late in gestation. Since CFTR has been suggested to play a role in water and nutrient exchange in the placenta through its interaction with aquaporins, we analyzed placental aquaporin expression in late-gestation CF and control littermates. While significant differences were observed in Aquaporin 9 expression in CF placentas in late gestation, there was no evidence of placental fluid exchange differences between CF and control littermates. The results from this study indicate that decreased IGF-1 levels are highly correlated with growth in CF mice, independent of CF intestinal obstruction. However, the perinatal growth deficits that are observed in CF mice are not due to decreased IGF-1 levels or differences in placenta-mediated fluid exchange. Further investigation is necessary to understand the etiology of early growth deficits in CF, as growth has been shown to be a significant factor in disease outcomes.

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Section: Resultsmentioning

confidence: 99%

Growth deficits in cystic fibrosis mice begin in utero prior to IGF-1 reduction

et al. 2017

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“…The use of a small glycopolymers to chelate Ca 2+ as a means to favorably alter mucus viscoelasticity in CF lung disease has been investigated recently (10)(11)(12). While this is mechanistically related to the effects described here, the use of a high-MW glycopolymer that interacts directly with mucins and the glycocalyx to displace Ca 2+ binding is a distinct approach.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of an environment rich in bicarbonate and sodium to remove and displace Ca 2+ , as occurs in the event of dysfunctional CF transmembrane regulator-mediated (CFTR-mediated) ion transport in CF and other lung diseases, mucins are unable to undergo normal posttranslational processing and expansion to their linear form, instead remaining compact, contributing to mucus that is hyperviscous, cohesive, and adhesive to the surface epithelium (7)(8)(9). Ca 2+ chelation has been investigated as an intervention to change the local ionic environment of airway mucus but has not yet been successful (7,(10)(11)(12)(13). In contrast, we postulated that a polycationic glycopolymer could modulate the mucin-mucin interactions mediated by Ca 2+ to create a solution phase of mucus with different adhesive and viscoelastic properties.…”

Section: Introductionmentioning

confidence: 99%

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus

Fernandez-Petty¹,

Hughes²,

Bowers³

et al. 2019

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“…Alginate, which disrupts the mucin-mucin interaction or the chelation of calcium ions (Ambort et al 2012), can be utilized to reduce the accumulation of intestinal mucus in mice with cystic fibrosis (CF). Vitko et al (2016) evaluated the therapeutic effect of alginate oligosaccharide, OligoG, on the CF mouse model. CF is caused by a mutation in the gene that encodes the CF transmembrane conductance regulator protein.…”

Section: Anti-cystic Fibrosis Activitymentioning

confidence: 99%

Marine polysaccharides: therapeutic efficacy and biomedical applications

et al. 2017

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The ocean contains numerous marine organisms, including algae, animals, and plants, from which diverse marine polysaccharides with useful physicochemical and biological properties can be extracted. In particular, fucoidan, carrageenan, alginate, and chitosan have been extensively investigated in pharmaceutical and biomedical fields owing to their desirable characteristics, such as biocompatibility, biodegradability, and bioactivity. Various therapeutic efficacies of marine polysaccharides have been elucidated, including the inhibition of cancer, inflammation, and viral infection. The therapeutic activities of these polysaccharides have been demonstrated in various settings, from in vitro laboratory-scale experiments to clinical trials. In addition, marine polysaccharides have been exploited for tissue engineering, the immobilization of biomolecules, and stent coating. Their ability to detect and respond to external stimuli, such as pH, temperature, and electric fields, has enabled their use in the design of novel drug delivery systems. Thus, along with the promising characteristics of marine polysaccharides, this review will comprehensively detail their various therapeutic, biomedical, and miscellaneous applications.

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A novel guluronate oligomer improves intestinal transit and survival in cystic fibrosis mice

Abstract: OligoG improves intestinal transit and survival in CF mice by reducing the accumulation of intestinal mucus. OligoG's ability to directly bind mucin, disrupt mucin interaction and/or sequester calcium allowing for mucin expansion may explain the decrease in mucus accumulation.

Cited by 23 publications

References 43 publications

Growth deficits in cystic fibrosis mice begin in utero prior to IGF-1 reduction

Growth deficits in cystic fibrosis mice begin in utero prior to IGF-1 reduction

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus

Marine polysaccharides: therapeutic efficacy and biomedical applications

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