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S-nitrosoglutathione accelerates recovery from 5-fluorouracil-induced oral mucositis.

Skeff MA, Brito GA, de Oliveira MG, Braga CM, Cavalcante MM, Baldim V, Holanda-Afonso RC, Silva-Boghossian CM, Colombo AP, Ribeiro RA, Moura-Neto V, Leitão RF - PLoS ONE (2014)

Bottom Line: The HPMC/GSNO formulations were found to provide sustained release of NO for more than 4 h at concentration-dependent rates of 14 to 80 nmol/mL/h.HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14.Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cell Morphogenesis, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.

ABSTRACT

Introduction: Mucositis induced by anti-neoplastic drugs is an important, dose-limiting and costly side-effect of cancer therapy.

Aim: To evaluate the effect of the topical application of S-nitrosoglutathione (GSNO), a nitric oxide donor, on 5-fluorouracil (5-FU)-induced oral mucositis in hamsters.

Materials and methods: Oral mucositis was induced in male hamsters by two intraperitoneal administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) followed by mechanical trauma on the fourth day. Animals received saline, HPMC or HPMC/GSNO (0.1, 0.5 or 2.0 mM) 1 h prior to the 5-FU injection and twice a day for 10 or 14 days. Samples of cheek pouches were harvested for: histopathological analysis, TNF-α and IL-1β levels, immunohistochemical staining for iNOS, TNF-α, IL-1β, Ki67 and TGF-β RII and a TUNEL assay. The presence and levels of 39 bacterial taxa were analyzed using the Checkerboard DNA-DNA hybridization method. The profiles of NO released from the HPMC/GSNO formulations were characterized using chemiluminescence.

Results: The HPMC/GSNO formulations were found to provide sustained release of NO for more than 4 h at concentration-dependent rates of 14 to 80 nmol/mL/h. Treatment with HPMC/GSNO (0.5 mM) significantly reduced mucosal damage, inflammatory alterations and cell death associated with 5-FU-induced oral mucositis on day 14 but not on day 10. HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14. In addition, we observed that the chemotherapy significantly increased the levels and/or prevalence of several bacterial species.

Conclusion: Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.

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Related in: MedlinePlus

Oral bacterial species evaluated in mucositis lesions of hamsters.Only species showing significant differences between groups are displayed. Left panel: mean bacterial counts using log 10; Right panel: frequency of detection, %. * denotes p<0.05 and † p≤0.001 between groups using the Kruskal Wallis test. The number of animals in each group was at least five.
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pone-0113378-g007: Oral bacterial species evaluated in mucositis lesions of hamsters.Only species showing significant differences between groups are displayed. Left panel: mean bacterial counts using log 10; Right panel: frequency of detection, %. * denotes p<0.05 and † p≤0.001 between groups using the Kruskal Wallis test. The number of animals in each group was at least five.

Mentions: The prevalence and the mean bacterial levels in the swabs obtained from the oral ulcers of the animals are presented in Fig. 7. Of all 39 bacterial genomic probes tested, only 21 and 19 species showed significant differences between groups in levels and frequency of detection, respectively (p<0.05, Kruskal-Wallis test). Actinomyces naeslundii I, Streptococcus constellatus, Eubacterium nodatum, Aggregatibacter actinomycetemcomitans, Treponema socranskii, Streptococcus sanguinis, Streptococcus oralis, Capnocytophaga ochracea, Actinomyces israelii, Treponema denticola, Prevotella nigrescens, Campylobacter showae, and Capnocytophaga gingivalis were not detected in any sample suggesting that they do not inhabit the oral cavity of hamsters under any circumstances. Conversely, Streptococcus intermedius, Streptococcus gordonii, Propionibacterium acnes, Leptotrichia buccalis, Campylobacter concisus, and Prevotella intermedia were detected in all samples. Comparisons between Healthy and MT groups showed similar prevalences of all species analyzed with the exception of Fusobacterium nucleatum nucleatum, Selenomonas noxia, and Veilonella parvula, which showed a lower prevalence in the Healthy group (p<0.05). These data suggest that mechanical trauma of cheek pouch tissue itself may affect the composition of oral microbiota because the MT group did not undergo 5-FU administration. However, chemotherapy led to a significant change in the composition of the microbial community and resulted in a significant increase in the levels and/or prevalence of several species (Porphyromonas gingivalis, Fusobacterium nucleatum vicentii, Campylobacter rectus, Parvimonas micra, Actinomyces oris, Fusobacterium nucleatum polymorphum, Fusobacterium periodonticum, S. gordonii, Tannerella forsythia, S. noxia, Eikenella corrodens, Gemella morbillorum, L buccalis, and C. concisus) compared with the MT group and the Healthy group (p<0.05). In contrast, Actinomyces gerencseriae, Neisseria mucosa, and Prevotella melaninogenica were present at significantly lower levels in the groups subjected to 5-FU treatment (0.5 mM HPMC/GSNO, Saline, and HPMC groups) compared with the MT and H groups (p<0.05).


S-nitrosoglutathione accelerates recovery from 5-fluorouracil-induced oral mucositis.

Skeff MA, Brito GA, de Oliveira MG, Braga CM, Cavalcante MM, Baldim V, Holanda-Afonso RC, Silva-Boghossian CM, Colombo AP, Ribeiro RA, Moura-Neto V, Leitão RF - PLoS ONE (2014)

Oral bacterial species evaluated in mucositis lesions of hamsters.Only species showing significant differences between groups are displayed. Left panel: mean bacterial counts using log 10; Right panel: frequency of detection, %. * denotes p<0.05 and † p≤0.001 between groups using the Kruskal Wallis test. The number of animals in each group was at least five.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257535&req=5

pone-0113378-g007: Oral bacterial species evaluated in mucositis lesions of hamsters.Only species showing significant differences between groups are displayed. Left panel: mean bacterial counts using log 10; Right panel: frequency of detection, %. * denotes p<0.05 and † p≤0.001 between groups using the Kruskal Wallis test. The number of animals in each group was at least five.
Mentions: The prevalence and the mean bacterial levels in the swabs obtained from the oral ulcers of the animals are presented in Fig. 7. Of all 39 bacterial genomic probes tested, only 21 and 19 species showed significant differences between groups in levels and frequency of detection, respectively (p<0.05, Kruskal-Wallis test). Actinomyces naeslundii I, Streptococcus constellatus, Eubacterium nodatum, Aggregatibacter actinomycetemcomitans, Treponema socranskii, Streptococcus sanguinis, Streptococcus oralis, Capnocytophaga ochracea, Actinomyces israelii, Treponema denticola, Prevotella nigrescens, Campylobacter showae, and Capnocytophaga gingivalis were not detected in any sample suggesting that they do not inhabit the oral cavity of hamsters under any circumstances. Conversely, Streptococcus intermedius, Streptococcus gordonii, Propionibacterium acnes, Leptotrichia buccalis, Campylobacter concisus, and Prevotella intermedia were detected in all samples. Comparisons between Healthy and MT groups showed similar prevalences of all species analyzed with the exception of Fusobacterium nucleatum nucleatum, Selenomonas noxia, and Veilonella parvula, which showed a lower prevalence in the Healthy group (p<0.05). These data suggest that mechanical trauma of cheek pouch tissue itself may affect the composition of oral microbiota because the MT group did not undergo 5-FU administration. However, chemotherapy led to a significant change in the composition of the microbial community and resulted in a significant increase in the levels and/or prevalence of several species (Porphyromonas gingivalis, Fusobacterium nucleatum vicentii, Campylobacter rectus, Parvimonas micra, Actinomyces oris, Fusobacterium nucleatum polymorphum, Fusobacterium periodonticum, S. gordonii, Tannerella forsythia, S. noxia, Eikenella corrodens, Gemella morbillorum, L buccalis, and C. concisus) compared with the MT group and the Healthy group (p<0.05). In contrast, Actinomyces gerencseriae, Neisseria mucosa, and Prevotella melaninogenica were present at significantly lower levels in the groups subjected to 5-FU treatment (0.5 mM HPMC/GSNO, Saline, and HPMC groups) compared with the MT and H groups (p<0.05).

Bottom Line: The HPMC/GSNO formulations were found to provide sustained release of NO for more than 4 h at concentration-dependent rates of 14 to 80 nmol/mL/h.HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14.Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cell Morphogenesis, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.

ABSTRACT

Introduction: Mucositis induced by anti-neoplastic drugs is an important, dose-limiting and costly side-effect of cancer therapy.

Aim: To evaluate the effect of the topical application of S-nitrosoglutathione (GSNO), a nitric oxide donor, on 5-fluorouracil (5-FU)-induced oral mucositis in hamsters.

Materials and methods: Oral mucositis was induced in male hamsters by two intraperitoneal administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) followed by mechanical trauma on the fourth day. Animals received saline, HPMC or HPMC/GSNO (0.1, 0.5 or 2.0 mM) 1 h prior to the 5-FU injection and twice a day for 10 or 14 days. Samples of cheek pouches were harvested for: histopathological analysis, TNF-α and IL-1β levels, immunohistochemical staining for iNOS, TNF-α, IL-1β, Ki67 and TGF-β RII and a TUNEL assay. The presence and levels of 39 bacterial taxa were analyzed using the Checkerboard DNA-DNA hybridization method. The profiles of NO released from the HPMC/GSNO formulations were characterized using chemiluminescence.

Results: The HPMC/GSNO formulations were found to provide sustained release of NO for more than 4 h at concentration-dependent rates of 14 to 80 nmol/mL/h. Treatment with HPMC/GSNO (0.5 mM) significantly reduced mucosal damage, inflammatory alterations and cell death associated with 5-FU-induced oral mucositis on day 14 but not on day 10. HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14. In addition, we observed that the chemotherapy significantly increased the levels and/or prevalence of several bacterial species.

Conclusion: Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.

Show MeSH
Related in: MedlinePlus