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Role of nitrite, urate and pepsin in the gastroprotective effects of saliva

Dietary nitrate is now recognized as an alternative substrate for nitric oxide (•NO) production in the gut. This novel pathway implies the sequential reduction of nitrate to nitrite, •NO and other bioactive nitrogen oxides but the physiological relevance of these oxidants has remained elusive. We ha...

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Autores principales: Rocha, Bárbara S., Lundberg, Jon O, Radi, Rafael, Laranjinha, João
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864375/
https://www.ncbi.nlm.nih.gov/pubmed/27156250
http://dx.doi.org/10.1016/j.redox.2016.04.002
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author Rocha, Bárbara S.
Lundberg, Jon O
Radi, Rafael
Laranjinha, João
author_facet Rocha, Bárbara S.
Lundberg, Jon O
Radi, Rafael
Laranjinha, João
author_sort Rocha, Bárbara S.
collection PubMed
description Dietary nitrate is now recognized as an alternative substrate for nitric oxide (•NO) production in the gut. This novel pathway implies the sequential reduction of nitrate to nitrite, •NO and other bioactive nitrogen oxides but the physiological relevance of these oxidants has remained elusive. We have previously shown that dietary nitrite fuels an hitherto unrecognized nitrating pathway at acidic gastric pH, through which pepsinogen is nitrated in the gastric mucosa, yielding a less active form of pepsin in vitro. Here, we demonstrate that pepsin is nitrated in vivo and explore the functional impact of protein nitration by means of peptic ulcer development. Upon administration of pentagastrin and human nitrite-rich saliva or sodium nitrite to rats, nitrated pepsin was detected in the animal's stomach by immunoprecipitation. •NO was measured in the gastric headspace before and after nitrite instillation by chemiluminescence. At the end of each procedure, the stomach's lesions, ranging from gastric erosions to haemorrhagic ulcers, were scored. Nitrite increased gastric •NO by 200-fold (p<0.05) and nitrated pepsin was detected both in the gastric juice and the mucosa (p<0.05). Exogenous urate, a scavenger of nitrogen dioxide radical, blunted •NO detection and inhibited pepsin nitration, suggesting an underlining free radical-dependent mechanism for nitration. Functionally, pepsin nitration prevented the development of gastric ulcers, as the lesions were only apparent when pepsin nitration was inhibited by urate. In sum, this work unravels a novel dietary-dependent nitrating pathway in which pepsin is nitrated and inactivated in the stomach, preventing the progression of gastric ulcers.
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spelling pubmed-48643752016-05-19 Role of nitrite, urate and pepsin in the gastroprotective effects of saliva Rocha, Bárbara S. Lundberg, Jon O Radi, Rafael Laranjinha, João Redox Biol Research Paper Dietary nitrate is now recognized as an alternative substrate for nitric oxide (•NO) production in the gut. This novel pathway implies the sequential reduction of nitrate to nitrite, •NO and other bioactive nitrogen oxides but the physiological relevance of these oxidants has remained elusive. We have previously shown that dietary nitrite fuels an hitherto unrecognized nitrating pathway at acidic gastric pH, through which pepsinogen is nitrated in the gastric mucosa, yielding a less active form of pepsin in vitro. Here, we demonstrate that pepsin is nitrated in vivo and explore the functional impact of protein nitration by means of peptic ulcer development. Upon administration of pentagastrin and human nitrite-rich saliva or sodium nitrite to rats, nitrated pepsin was detected in the animal's stomach by immunoprecipitation. •NO was measured in the gastric headspace before and after nitrite instillation by chemiluminescence. At the end of each procedure, the stomach's lesions, ranging from gastric erosions to haemorrhagic ulcers, were scored. Nitrite increased gastric •NO by 200-fold (p<0.05) and nitrated pepsin was detected both in the gastric juice and the mucosa (p<0.05). Exogenous urate, a scavenger of nitrogen dioxide radical, blunted •NO detection and inhibited pepsin nitration, suggesting an underlining free radical-dependent mechanism for nitration. Functionally, pepsin nitration prevented the development of gastric ulcers, as the lesions were only apparent when pepsin nitration was inhibited by urate. In sum, this work unravels a novel dietary-dependent nitrating pathway in which pepsin is nitrated and inactivated in the stomach, preventing the progression of gastric ulcers. Elsevier 2016-04-08 /pmc/articles/PMC4864375/ /pubmed/27156250 http://dx.doi.org/10.1016/j.redox.2016.04.002 Text en © 2016 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Rocha, Bárbara S.
Lundberg, Jon O
Radi, Rafael
Laranjinha, João
Role of nitrite, urate and pepsin in the gastroprotective effects of saliva
title Role of nitrite, urate and pepsin in the gastroprotective effects of saliva
title_full Role of nitrite, urate and pepsin in the gastroprotective effects of saliva
title_fullStr Role of nitrite, urate and pepsin in the gastroprotective effects of saliva
title_full_unstemmed Role of nitrite, urate and pepsin in the gastroprotective effects of saliva
title_short Role of nitrite, urate and pepsin in the gastroprotective effects of saliva
title_sort role of nitrite, urate and pepsin in the gastroprotective effects of saliva
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864375/
https://www.ncbi.nlm.nih.gov/pubmed/27156250
http://dx.doi.org/10.1016/j.redox.2016.04.002
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