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Summary Nitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. We demonstrate that NO derived from enterocytes alleviates colitis by decreasing macrophage infiltration and tissue damage, whereas immune cell-derived NO is associated with macrophage activation, resulting in increased severity of inflammation. We find that induction of endogenous NO production by enterocytes with supplements that upregulate ASL expression and complement its substrates results in improved epithelial integrity and alleviation of colitis and of inflammation-associated colon cancer. [ABSTRACT FROM AUTHOR]

Cytochrome c (cyt c)-derived protein radicals, radical adduct aggregates, and protein tyrosine nitration have been implicated in the pro-apoptotic event connecting inflammation to the development of diseases. During inflammation, one of the reactive oxygen species metabolized via neutrophil activation is hypochlorite (HOCl); destruction of the mitochondrial electron transport chain by hypochlorite is considered to be a damaging factor. Previous study has shown that HOCl induces the site-specific oxidation of cyt c at met-80. In this work, we have assessed the hypothesis that exposure of cyt c to physiologically relevant concentrations of HOCl leads to protein-derived radical and consequent protein aggregation, which subsequently affects cyt c′s regulation of nitric oxide metabolism. Reaction intermediates, chemical pathways available for protein aggregation, and protein nitration were examined. A weak ESR signal for immobilized nitroxide derived from the protein was detected when a high concentration of cyt c was reacted with hypochlorite in the presence of the nitroso spin trap 2-methyl-2-nitrosopropane. When a low concentration of cyt c was exposed to the physiologically relevant levels of HOCl in the presence of 5,5-dimethyl-pyrroline N-oxide (DMPO), we detected DMPO nitrone adducts derived from both protein and protein aggregate radicals as assessed by Western blot using an antibody raised against the DMPO nitrone adduct. The cyt c-derived protein radicals formed by HOCl were located on lysine and tyrosine residues, with lysine predominating. Cyt c-derived protein aggregates induced by HOCl involved primarily lysine residues and hydrophobic interaction. In addition, HOCl-oxidized cyt c (HOCl-cyt c) exhibited a higher affinity for NO and enhancement of nonenzymatic NO synthesis from nitrite reduction. Furthermore, HOCl-mediated cyt c oxidation also resulted in a significant elevation of cyt c nitration derived from either NO trapping of the cyt c-derived tyrosyl radical or cyt c-catalyzed one-electron oxidation of nitrite. [Copyright &y& Elsevier]

• The AlaxoLito Plus Nasal Stent does not increase exercise performance or oxygen uptake. • RBC deformability changes depending on breathing mode and intensity. • Exhaled NO increases with stent applications compared to oral/nasal breathing. • Blood NO concentrations are not affected. To investigate the influence of the intranasal AlaxoLito Plus Nasal Stent during exercise on nitric oxide (NO) synthesis, NO exhalation, red blood cell (RBC) deformability and oxygen uptake. Parameters were measured before and after acute cycle ergometer test at different intensities. Spirometric, microrheological and NO parameters were determined for oral (OB), nasal (NB) and nasal-stent breathing (SB). RBC deformability was measured and elongation indices for 3.87 Pa and maximal deformability were calculated. RBC/plasma/exhaled NO, oxygen uptake and respiratory rate were determined. Exhaled NO was higher at rest during OB compared to SB and NB and decreased after exercise with NB and SB. Plasma and RBC NO remained unaltered during intervention. RBC deformability increased at moderate intensity during SB. Deformability decreased at moderate and medium intensity with NB. Respiratory rate for same oxygen uptake did not differ between breathing settings. The AlaxoLito Plus Nasal Stent may modulate deformability during moderate exercise and increase NO exhalation without major effects on oxygen uptake and performance. [ABSTRACT FROM AUTHOR]