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

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-trophi...

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Published in:	Brazilian journal of medical and biological research Vol. 48; no. 6; pp. 493 - 501
Main Authors:	Araújo, C V, Lazzarotto, C R, Aquino, C C, Figueiredo, I L, Costa, T B, Alves, L A de Oliveira, Ribeiro, R A, Bertolini, L R, Lima, A A M, Brito, G A C, Oriá, R B
Format:	Journal Article
Language:	English
Published:	Brazil Associacao Brasileira de Divulgacao Cientifica (ABDC) 01-06-2015 Associação Brasileira de Divulgação Científica
Subjects:	5-Fluorouracil Alanyl-glutamine Animals Antimetabolites, Antineoplastic - adverse effects Apolipoprotein E Apolipoproteins Apolipoproteins E - deficiency Apoptosis - drug effects BIOLOGY Biomedical Sciences Body Weight Care and treatment Complications and side effects Dipeptides - pharmacology Dipeptides - therapeutic use Dosage and administration Female Fluorouracil Fluorouracil - adverse effects Health aspects Insulin-Like Growth Factor I - analysis Intestinal Mucosa - drug effects Intestinal Mucosa - pathology Leukocyte Count Lymphoma, B-Cell Lymphomas Male MEDICINE, RESEARCH & EXPERIMENTAL mice Mice, Inbred C57BL Mitosis - drug effects Mucositis Mucositis - chemically induced Mucositis - drug therapy Mucositis - pathology Random Allocation Real-Time Polymerase Chain Reaction Reproducibility of Results Risk factors RNA Time Factors Treatment Outcome Brazil mucositis 5-Fluorouracil Apolipoprotein E mice Alanyl-glutamine
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Summary:	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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ISSN:	0100-879X 1414-431X 1414-431X
DOI:	10.1590/1414-431X20144360