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. 2019 Jan 1;60(1):7-16.
doi: 10.1093/jrr/rry076.

Purified PEGylated human glucagon-like peptide-2 reduces the severity of irradiation-induced acute radiation enteritis in rats

Tian Zhang  1 , Lei Shi  1 , Yuan Xu  1 , Yang Li  1 , Shicao Li  1 , Bo Guan  1 , Zhihua Qi  1 , Ye Zhang  2 , Linna Liu  1
Affiliations

Purified PEGylated human glucagon-like peptide-2 reduces the severity of irradiation-induced acute radiation enteritis in rats

Tian Zhang et al. J Radiat Res. .

Abstract

Radiation-induced acute intestinal injury after abdominal and pelvic irradiation is a common and serious problem in the clinical setting. Glucagon-like peptide-2 (GLP-2), a 33-amino acid peptide, exerts diverse effects related to the regulation of gastrointestinal growth and function. However, GLP-2 is relatively unstable in vivo. The aim of the present study was to improve GLP-2 stability in vivo and to evaluate its therapeutic effect on acute radiation enteritis. We generated long-lasting intestinal protection peptides by conjugating human GLP-2 (hGLP-2) peptides to polyethyleneglycol (PEG) to produce mPEGylation hGLP-2 (Mono-PEG-hGLP-2) through an enzymatic site-specific transglutamination reaction. Mono-PEG-hGLP-2 synthesized under optimal reaction conditions and separated by one-step ion-exchange chromatography was found to be resistant to degradation in vitro. Pretreatment with Mono-PEG-hGLP-2 reduced the severity of radiation-induced intestinal injury, oxidative stress, and the expression of NF-κB in rats with irradiation-induced acute radiation enteritis. The enhanced biological potency of Mono-PEG-hGLP-2 highlights its potential as a therapeutic agent for intestinal diseases.

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Figures

Fig. 1.
Fig. 1.
(a) Mono-PEG-hGLP-2 yield in different molar ratios of mPEG-SPA to pGLP-2, *P < 0.05 vs the molar ratio of mPEG-SPA to pGLP-2, 2:1. (b) The conversion ratio of Mono-PEG-hGLP-2 in different concentrations of GLP-2, *P < 0.05 vs the concentration of GLP-2 in 1 mg/ml. (c) Influence of reaction temperature and reaction time on the yield of Mono-PEG-hGLP-2. (d) Proteolytic stability of Mono-PEG-hGLP-2 and GLP-2.
Fig. 2.
Fig. 2.
(a) Reverse-phase high-performance liquid chromatography profiles of GLP-2, reaction mixture, and sediment of reaction; (b) high-performance gel filtration liquid chromatography of purified Mono-PEG-GLP-2 by reverse-phase high-performance liquid chromatography. The purity of Mono-PEG-GLP-2 was 97% and the yield was 95%.
Fig. 3.
Fig. 3.
Histological and morphometric changes in small intestinal villi of the rats. MPG2-L: pretreated with 3 μg of Mono-PEG-hGLP-2. MPG2-M: pretreated with 10 μg of Mono-PEG-hGLP-2. MPG2-H: pretreated with 30 μg of Mono-PEG-hGLP-2.
Fig. 4.
Fig. 4.
Immunohistochemical (a) and Western blot analysis (b) of NF-κB in intestines. MPG2-L: pretreated with 3 μg of Mono-PEG-hGLP-2; MPG2-M: pretreated with 10 μg of Mono-PEG-hGLP-2; MPG2-H: pretreated with 30 μg of Mono-PEG-hGLP-2, *P < 0.05, **P < 0.01 vs model.
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