Luminal oxidants selectively modulate electrogenic ion transport in rat colon

Mayol, Julio; Adame-Navarrete, Yolanda; Alarma-Estrany, Pilar; Roldán, Elena Molina; Huete-Toral, Fernando; Fernandez-Represa, Jesus A.

doi:10.3748/wjg.v12.i34.5523

Cited by 12 publications

(16 citation statements)

References 14 publications

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“…1A and B). This agrees with previously published data suggesting that exposure to 5 to 10 M Mtz induces a 25% reduction in cell growth over 24 h (15) and that 1 mM is a physiologically relevant concentration of H 2 O 2 (43,44). Incubation at either 39 or 41°C resulted in an approximate 30% reduction in cell number; however, as incubation at 42°C was highly detrimental, 39°C was selected as the more conservative condition for further experimentation (Fig.…”

Section: Resultssupporting

confidence: 90%

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Ansell

McConville

Baker

et al. 2016

Antimicrob Agents Chemother

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dUnderstanding how parasites respond to stress can help to identify essential biological processes. Giardia duodenalis is a parasitic protist that infects the human gastrointestinal tract and causes 200 to 300 million cases of diarrhea annually. Metronidazole, a major antigiardial drug, is thought to cause oxidative damage within the infective trophozoite form. However, treatment efficacy is suboptimal, due partly to metronidazole-resistant infections. To elucidate conserved and stress-specific responses, we calibrated sublethal metronidazole, hydrogen peroxide, and thermal stresses to exert approximately equal pressure on trophozoite growth and compared transcriptional responses after 24 h of exposure. We identified 252 genes that were differentially transcribed in response to all three stressors, including glycolytic and DNA repair enzymes, a mitogen-activated protein (MAP) kinase, high-cysteine membrane proteins, flavin adenine dinucleotide (FAD) synthetase, and histone modification enzymes. Transcriptional responses appeared to diverge according to physiological or xenobiotic stress. Downregulation of the antioxidant system and ␣-giardins was observed only under metronidazole-induced stress, whereas upregulation of GARP-like transcription factors and their subordinate genes was observed in response to hydrogen peroxide and thermal stressors. Limited evidence was found in support of stress-specific response elements upstream of differentially transcribed genes; however, antisense derepression and differential regulation of RNA interference machinery suggest multiple epigenetic mechanisms of transcriptional control. Giardia duodenalis (synonyms, Giardia lamblia and Giardia intestinalis) is a parasitic protist of the vertebrate gastrointestinal tract and the most common parasite of humans (1). The vegetative life cycle stage (trophozoite) infects around 1 billion people and causes 200 to 300 million cases of diarrheal disease (giardiasis) each year (1). Infection with G. duodenalis is also associated with the development of chronic diseases such as irritable bowel syndrome, chronic fatigue, and diabetes (2). At present, only two major drug classes are available to treat giardiasis: nitroimidazoles, primarily metronidazole (Mtz), and benzimidazoles, such as albendazole (3,4). Resistance to Mtz is documented in treatment-resistant clinical isolates (5-8), and resistant lines can be generated in vitro (reviewed in reference 9).The mechanism of action of Mtz is relatively poorly understood. This compound is thought to diffuse into G. duodenalis trophozoites as an inactive prodrug, whereupon it is enzymatically reduced (activated), yielding reactive intermediates. Mtz intermediates are thought to kill trophozoites by oxidizing proteins, lipids, and DNA (10, 11); however, the relative importance of damage to different biomolecules for Mtz-induced cytotoxicity is contested (10, 12). Resistance to Mtz involves changes in enzyme expression which limit drug activation. Nitroreductase-1, thioredoxin reductase, and pyruvat...

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Section: Resultssupporting

confidence: 90%

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Ansell

McConville

Baker

et al. 2016

Antimicrob Agents Chemother

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“…Luminal exposure to H 2 O 2 was shown to stimulate basal chloride secretion. In contrast to the observed stimulatory effect on basal secretion, cAMPstimulated electrogenic ion transport was blunted by luminal H 2 O 2 which may indicate an effect on CFTR function [105].…”

Section: Ion Channels Regulating Fluid Distributioncontrasting

confidence: 64%

Ion channels in inflammation

Eisenhut

Wallace

2011

Pflugers Arch - Eur J Physiol

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Most physical illness in vertebrates involves inflammation. Inflammation causes disease by fluid shifts across cell membranes and cell layers, changes in muscle function and generation of pain. These disease processes can be explained by changes in numbers or function of ion channels. Changes in ion channels have been detected in diarrhoeal illnesses, pyelonephritis, allergy, acute lung injury and systemic inflammatory response syndromes involving septic shock. The key role played by changes in ion transport is directly evident in inflammation-induced pain. Expression or function of all major categories of ion channels like sodium, chloride, calcium, potassium, transient receptor potential, purinergic receptor and acid-sensing ion channels can be influenced by cyto- and chemokines, prostaglandins, leukotrienes, histamine, ATP, reactive oxygen species and protons released in inflammation. Key pathways in this interaction are cyclic nucleotide, phosphoinositide and mitogen-activated protein kinase-mediated signalling, direct modification by reactive oxygen species like nitric oxide, ATP or protons and disruption of the cytoskeleton. Therapeutic interventions to modulate the adverse and overlapping effects of the numerous different inflammatory mediators on each ion transport system need to target adversely affected ion transport systems directly and locally.

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“…In order to investigate whether a paracellular ion flux could contribute to the VCC-induced R T reduction, the permeability of colon mucosa was assessed by mucosal-to-serosal FITC flux [29]. Fig.…”

Section: Resultsmentioning

confidence: 99%

The Vibrio cholerae Cytolysin Promotes Chloride Secretion from Intact Human Intestinal Mucosa

et al. 2009

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BackgroundThe pathogenicity of the Vibrio cholerae strains belonging to serogroup O1 and O139 is due to the production of virulence factors such as cholera toxin (CT) and the toxin-coregulated pilus (TCP). The remaining serogroups, which mostly lack CT and TCP, are more frequently isolated from aquatic environmental sources than from clinical samples; nevertheless, these strains have been reported to cause human disease, such as sporadic outbreaks of watery diarrhoea and inflammatory enterocolitis. This evidence suggested the possibility that other virulence factor(s) than cholera toxin might be crucial in the pathogenesis of Vibrio cholerae-induced diarrhoea, but their nature remains unknown. VCC, the hemolysin produced by virtually all Vibrio cholerae strains, has been proposed as a possible candidate, though a clear-cut demonstration attesting VCC as crucial in the pathogenesis of Vibrio cholerae-induced diarrhoea is still lacking.Methodology/Principal FindingsElectrophysiological parameters and paracellular permeability of stripped human healthy colon tissues, obtained at subtotal colectomy, mounted in Ussing chamber were studied in the presence or absence of VCC purified from culture supernatants of V. cholerae O1 El Tor strain. Short circuit current (ISC) and transepithelial resistance (RT) were measured by a computerized voltage clamp system. The exposure of sigmoid colon specimens to 1 nM VCC resulted in an increase of ISC by 20.7%, with respect to the basal values, while RT was reduced by 12.3%. Moreover, increase in ISC was abolished by bilateral Cl− reduction.Conclusion/SignificanceOur results demonstrate that VCC, by forming anion channels on the apical membrane of enterocytes, triggers an outward transcellular flux of chloride. Such an ion movement, associated with the outward movement of Na+ and water, might be responsible for the diarrhoea caused by the non-toxigenic strains of Vibrio cholerae.

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Luminal oxidants selectively modulate electrogenic ion transport in rat colon

Abstract: H2O(2) may be an important selective modulator of intestinal ion and water secretion in certain pathologic conditions such as inflammation or ischemia-reperfusion by multiple mechanisms.

Cited by 12 publications

References 14 publications

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Ion channels in inflammation

The Vibrio cholerae Cytolysin Promotes Chloride Secretion from Intact Human Intestinal Mucosa

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