Delivery of two-step transcription amplification exendin-4 plasmid system with arginine-grafted bioreducible polymer in type 2 diabetes animal model.
Delivery of two-step transcription amplification exendin-4 plasmid system with arginine-grafted bioreducible polymer in type 2 diabetes animal model.
复制标题
DOI：
10.1016/j.jconrel.2012.06.010
复制
发表时间：
2012-08-20
期刊：
影响因子：
--
通讯作者：
Kim SW
中科院分区：
文献类型：
--
作者：
Kim PH;Lee M;Kim SW
Exendin-4 是胰高血糖素样肽 1 (GLP-1) 受体激动剂，是一种外分泌激素，具有与 GLP-1 类似的有效促胰岛素作用，例如刺激胰岛素生物合成、促进葡萄糖浓度依赖性胰岛素分泌、减缓胃排空、减少食物摄入和刺激 β 细胞增殖。 Exendin-4 的半衰期也比 GLP-1 更长，因为它能抵抗二肽基肽酶 IV (DPP-IV) 的降解。尽管其作为糖尿病治疗剂具有许多优点，但其临床应用仍然受到限制。因此，为了提高Exendin-4的体内活性，开发了基因治疗系统作为替代方法。利用两步转录扩增（TSTA）系统构建了exendin-4表达系统，该系统由pβ-Gal4-p65和pUAS-SP-exendin-4组成，结合信号肽（SP）的优点，以利于其在异位细胞或组织中的分泌。精氨酸接枝的环胺双丙烯酰胺-二氨基己烷聚合物(ABP)被用作基因载体。在递送 ABP/TSTA-SP-exendin-4 后，在体外评估了 exendin-4 表达的增加、NIT-1 胰岛素瘤细胞中葡萄糖依赖性胰岛素分泌以及 DPP-IV 存在下的高胰岛素表达。单次静脉注射ABP/TSTA-SP-exendin-4后，糖尿病小鼠的血糖水平从实验期第三天起急剧下降。与其他组相比，注射后第 3 天开始，在 ABP/TSTA/SP-exendin-4 处理的小鼠组中也观察到了 exendin-4 的最高促胰岛素作用。具有SP和ABP聚合物的TSTA exendin-4表达系统具有治疗2型糖尿病的潜在基因疗法。
Exendin-4, glucagon-like peptide 1 (GLP-1) receptor agonist, is an exocrine hormone, which has potent insulinotropic actions similar to GLP-1 such as stimulating insulin biosynthesis, facilitating glucose-concentration dependent insulin secretion, slowing gastric emptying, reducing food intake and stimulating β-cell proliferation. Exendin-4, also, has a longer half-life than GLP-1, due to itsresistance to degradation by dipeptidyl peptidase IV (DPP-IV). In spite of its many advantages as a therapeutic agent for diabetes, its clinical application is still restricted. Thus, to improve the activity of exendin-4 in vivo, gene therapy system was developed as an alternative method. An exendin-4 expression system was constructed using the two-step transcription amplification (TSTA) system, which is composed of pβ-Gal4-p65 and pUAS-SP-exendin-4 with combining the advantages of signal peptide (SP) in order to facilitate its secretion in ectopic cells or tissue. Arginine-grafted cyctaminebisacrylamide-diaminohexane polymer (ABP) was used as a gene carrier. Increased expression of exendin-4, glucose dependent insulin secretion in NIT-1 insulinoma cells, and high insulin expression in the presence of DPP-IV were evaluated in vitro after delivery of ABP/TSTA-SP-exendin-4. Blood glucose levels in diabetic mice were decreased dramatically from the third day for experimental period after single intravenous administration with ABP/TSTA-SP-exendin-4. The highest insulinotropic effect of exendin-4 was also observed in the ABP/TSTA/SP-exendin-4-treated mice groups, compared with the others groups from the 3rd day after injection. TSTA exendin-4 expression system with SP and ABP polymer has a potential gene therapy for the treatment of type 2 diabetes.
登录
查看更多内容
影响因子：
7.7
作者：
Martin B;Golden E;Carlson OD;Pistell P;Zhou J;Kim W;Frank BP;Thomas S;Chadwick WA;Greig NH;Bates GP;Sathasivam K;Bernier M;Maudsley S;Mattson MP;Egan JM
通讯作者：
Egan JM
DOI：
10.1590/s0004-27302008000600016
发表时间：
2008-08-01
期刊：
Arquivos Brasileiros de Endocrinologia & Metabologia
影响因子：
--
作者：
Davidson, Jaime A.;Parente, Erika B.;Gross, Jorge L.
通讯作者：
Gross, Jorge L.
影响因子：
4.5
作者：
Kim, Hyun Ah;Lee, Suyeon;Lee, Minhyung
通讯作者：
Lee, Minhyung
影响因子：
12.4
作者：
Choi, S;Oh, S;Kim, SW
通讯作者：
Kim, SW
影响因子：
5.9
作者：
Kim SW
通讯作者：
Kim SW