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Logo of bmcgastBioMed Centralsearchsubmit a manuscriptregisterthis articleBMC Gastroenterology
 
BMC Gastroenterol. 2012; 12: 35.
Published online Jul 13, 2012. doi:  10.1186/1471-230X-12-35
PMCID: PMC3398852
Apolipoprotein E COG 133 mimetic peptide improves 5-fluorouracil-induced intestinal mucositis
Orleâncio Gomes R Azevedo,1,2 Renato André C Oliveira,1,2 Bruna Castro Oliveira,1,2 Snjezana Zaja-Milatovic,1 Celina Viana Araújo,2 Deysi Viviana T Wong,4 Tiê Bezerra Costa,2 Herene Barros Miranda Lucena,1 Roberto César P Lima-Júnior,4 Ronaldo A Ribeiro,4 Cirle A Warren,1 Aldo Ângelo M Lima,1,2 Michael P Vitek,3 Richard L Guerrant,1 and Reinaldo B Oriácorresponding author1,2
1Center for Global Health, School of Medicine, University of Virginia, Carter Harrison Bldg MR-6, 625 Crispell Drive, Room 2526, Charlottesville, VA, 22908, USA
2Laboratoy of the Biology of Tissue Healing, Ontogeny and Nutrition, Institute of the Brazilian Semi-arid, School of Medicine, Federal University of Ceara, Rua Coronel Nunes de Melo, 1315 Rodolfo Teófilo, Fortaleza, Ceará, 60.430-270, Brazil
3Cognosci Inc., Duke University, Research Triangle Park, Durham, NC, USA
4Laboratory of Inflammation and Cancer, School of Medicine, Federal University of Ceara, Rua Coronel Nunes de Melo, 1315 Rodolfo Teófilo, Fortaleza, Ceará, 60.430-270, Brazil
corresponding authorCorresponding author.
Orleâncio Gomes R Azevedo: or6f/at/virginia.edu; Renato André C Oliveira: renatandre/at/hotmail.com; Bruna Castro Oliveira: castrobruna/at/hotmail.com; Snjezana Zaja-Milatovic: sz7s/at/virginia.edu; Celina Viana Araújo: celina_araujo/at/yahoo.com.br; Deysi Viviana T Wong: devite06/at/gmail.com; Tiê Bezerra Costa: tiecosta/at/yahoo.com.br; Herene Barros Miranda Lucena: herenelucena/at/hotmail.com; Roberto César P Lima-Júnior: robertocesar/at/ufc.br; Ronaldo A Ribeiro: ribeiror/at/ufc.br; Cirle A Warren: ca6t/at/virginia.edu; Aldo Ângelo M Lima: alima/at/ufc.br; Michael P Vitek: mvitek/at/bellsouth.net; Richard L Guerrant: rlg9a/at/virginia.edu; Reinaldo B Oriá: rbo5u/at/virginia.edu
Received June 21, 2011; Accepted April 23, 2012.
Abstract
Background
Intestinal mucositis is one of the major troublesome side effects of anticancer chemotherapy leading to poor patient compliance. In this study we addressed the role of the novel apolipoprotein E (ApoE) COG 133 mimetic peptide in 5-fluorouracil (5-FU)-challenged Swiss mice and IEC-6 cell monolayers. Experiments were also conducted in C57BL6J ApoE knock-out mice to assess the effects of apoE peptide treatment.
Methods
Experimental groups were as follows: unchallenged controls, 5-FU-challenged mice (450 mg/kg, i.p) with or without the ApoE peptide (0.3, 1, and 3 μM, given twice daily i.p. for 4 days). Mice were sacrificed 3 days after 5-FU challenge. Proximal small intestinal samples were harvested for molecular biology and histological processing. We conducted ELISA assays and RT-PCR to target IL-1β, TNF-α, IL-10, iNOS, and myeloperoxidase (MPO) to assess intestinal inflammation. Cell death and NF-κB assays were also conducted in apoE knock-out mice. In our in vitro models, IEC-6 cells were exposed to 1 mM of 5-FU in glutamine free media with or without the ApoE peptide (0.02, 0.2, 2, 5, 10, and 20 μM). We investigated IEC-6 cell proliferation and migration, 24 h after the 5-FU challenge. Additionally, apoptotic IEC-6 cells were measured by Tunel and flow cytometry. Equimolar doses of the ApoA-I (D4-F) peptide were also used in some experiments for comparative studies.
Results
Villus blunting and heavy inflammatory infiltrates were seen in the 5-FU-challenged group, findings that were partially ameliorated by the ApoE peptide. We found increased intestinal MPO and pro-inflammatory IL-1β and TNF-α levels, and TNF-α and iNOS transcripts, and reduction of IL-10 following 5-FU treatment, each of which were partially abrogated by the peptide. Improvements were also found in IEC-6 cell apoptosis and migration following ApoE and D-4F treatment.
Conclusion
Altogether, these findings suggest that the novel ApoE COG 133 mimetic peptide can reduce 5-FU-induced intestinal changes and potentially benefit mucositis.
Keywords: Mucositis, Apolipoprotein E, 5-fluorouracil, Inflammation, Cytokines
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