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Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice.

Araújo CV, Lazzarotto CR, Aquino CC, Figueiredo IL, Costa TB, Alves LA, Ribeiro RA, Bertolini LR, Lima AA, Brito GA, Oriá RB - Braz. J. Med. Biol. Res. (2015)

Bottom Line: Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury.Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls.Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge.

View Article: PubMed Central - PubMed

Affiliation: Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil.

ABSTRACT
Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/-) and wild-type (APOE+/+) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE-/- mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE+/+ mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE-/- -challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge.

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Quantitative real-time PCR for B-cell lymphoma 2 (Bcl-2) and insulin-likegrowth factor-1 (IGF-1) mRNA transcripts from C57BL6J ApoE-knockout(APOE-/-) and wild-type (APOE+/+) mice challenged by5-fluorouracil (5-FU)-induced intestinal mucositis (450 mg/kg,ip, single dose) on the day 6 post-challenge and treatedwith alanyl-glutamine (Ala-Gln, 100 mM) or phosphate buffered saline (PBS,control) via gavage. Data are reported as means±SEM. aP<0.05vs 5-FU-challenged group. bP<0.05vs unchallenged control (one-way ANOVA and the Bonferronitest).
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f05: Quantitative real-time PCR for B-cell lymphoma 2 (Bcl-2) and insulin-likegrowth factor-1 (IGF-1) mRNA transcripts from C57BL6J ApoE-knockout(APOE-/-) and wild-type (APOE+/+) mice challenged by5-fluorouracil (5-FU)-induced intestinal mucositis (450 mg/kg,ip, single dose) on the day 6 post-challenge and treatedwith alanyl-glutamine (Ala-Gln, 100 mM) or phosphate buffered saline (PBS,control) via gavage. Data are reported as means±SEM. aP<0.05vs 5-FU-challenged group. bP<0.05vs unchallenged control (one-way ANOVA and the Bonferronitest).

Mentions: No statistical differences were found in the ileal IGF-1 and Bcl-2 mRNA transcripts 5days after 5-FU injection in APOE+/+ mice compared with the unchallengedcontrols. Ala-Gln treatment raised ileal Bcl-2 transcripts following 5-FU challengein the APOE-/- mice. Noteworthy, 5-FU caused a significant reduction inthe ileal IGF-1 mRNA transcripts at 5 days post-challenge only in theAPOE-/- mouse strain (P<0.05), an effect that was improved byAla-Gln (100 mM) treatment (see Figure 5).


Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice.

Araújo CV, Lazzarotto CR, Aquino CC, Figueiredo IL, Costa TB, Alves LA, Ribeiro RA, Bertolini LR, Lima AA, Brito GA, Oriá RB - Braz. J. Med. Biol. Res. (2015)

Quantitative real-time PCR for B-cell lymphoma 2 (Bcl-2) and insulin-likegrowth factor-1 (IGF-1) mRNA transcripts from C57BL6J ApoE-knockout(APOE-/-) and wild-type (APOE+/+) mice challenged by5-fluorouracil (5-FU)-induced intestinal mucositis (450 mg/kg,ip, single dose) on the day 6 post-challenge and treatedwith alanyl-glutamine (Ala-Gln, 100 mM) or phosphate buffered saline (PBS,control) via gavage. Data are reported as means±SEM. aP<0.05vs 5-FU-challenged group. bP<0.05vs unchallenged control (one-way ANOVA and the Bonferronitest).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4470307&req=5

f05: Quantitative real-time PCR for B-cell lymphoma 2 (Bcl-2) and insulin-likegrowth factor-1 (IGF-1) mRNA transcripts from C57BL6J ApoE-knockout(APOE-/-) and wild-type (APOE+/+) mice challenged by5-fluorouracil (5-FU)-induced intestinal mucositis (450 mg/kg,ip, single dose) on the day 6 post-challenge and treatedwith alanyl-glutamine (Ala-Gln, 100 mM) or phosphate buffered saline (PBS,control) via gavage. Data are reported as means±SEM. aP<0.05vs 5-FU-challenged group. bP<0.05vs unchallenged control (one-way ANOVA and the Bonferronitest).
Mentions: No statistical differences were found in the ileal IGF-1 and Bcl-2 mRNA transcripts 5days after 5-FU injection in APOE+/+ mice compared with the unchallengedcontrols. Ala-Gln treatment raised ileal Bcl-2 transcripts following 5-FU challengein the APOE-/- mice. Noteworthy, 5-FU caused a significant reduction inthe ileal IGF-1 mRNA transcripts at 5 days post-challenge only in theAPOE-/- mouse strain (P<0.05), an effect that was improved byAla-Gln (100 mM) treatment (see Figure 5).

Bottom Line: Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury.Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls.Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge.

View Article: PubMed Central - PubMed

Affiliation: Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil.

ABSTRACT
Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/-) and wild-type (APOE+/+) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE-/- mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE+/+ mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE-/- -challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge.

Show MeSH
Related in: MedlinePlus