Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
Normandy University, COBRA, UMR 6014 & FR 3038, Université de Rouen, INSA, Rouen, France.
J Pept Sci. 2019 Apr;25(4):e3153. doi: 10.1002/psc.3153. Epub 2019 Feb 7.
The aim of the study was to determine the in vitro immunomodulatory, cytotoxic, and insulin-releasing activities of seven phylloseptin-TR peptides and plasticin-TR, first isolated from the frog Phyllomedusa trinitatis. The most cationic peptides, phylloseptin-1.1TR and phylloseptin-3.1TR, showed greatest cytotoxic potency against A549, MDA-MB231, and HT-29 human tumor-derived cells and against mouse erythrocytes. Phylloseptin-4TR was the most hydrophobic and the most effective peptide at inhibiting production of the proinflammatory cytokines TNF-α and IL-1β by mouse peritoneal cells but was without effect on production of the antiinflammatory cytokine IL-10. Phylloseptin-2.1TR and phylloseptin-3.3TR were the most effective at stimulating the production of IL-10. The noncytotoxic peptide, plasticin-TR, inhibited production of TNF-α and IL-1β but was without effect on IL-10 production. The results of CD spectroscopy suggest that the different properties of plasticin-TR compared with the immunostimulatory activities of the previously characterized plasticin-L1 from Leptodactylus laticeps may arise from greater ability of plasticin-TR to oligomerize and adopt a stable helical conformation in a membrane-mimetic environment. All peptides stimulated release of insulin from BRIN-BD11 rat clonal β cells with phylloseptin-3.2TR being the most potent and effective and phylloseptin-2.1TR the least effective suggesting that insulinotropic potency correlates inversely with helicity. The study has provided insight into structure-activity relationships among the phylloseptins. The combination of immunomodulatory and insulinotropic activities together with low cytotoxicity suggests that phylloseptin-3.3TR and plasticin-TR may represent templates for the development of agents for use in antiinflammatory and type 2 diabetes therapies.
本研究旨在确定从青蛙 Phyllomedusa trinitatis 中首次分离出的七种 phylloseptin-TR 肽和 plastin-TR 的体外免疫调节、细胞毒性和胰岛素释放活性。阳离子性最强的肽 phylloseptin-1.1TR 和 phylloseptin-3.1TR 对 A549、MDA-MB231 和 HT-29 人肿瘤衍生细胞和小鼠红细胞显示出最大的细胞毒性。Phylloseptin-4TR 是最疏水的肽，也是抑制小鼠腹腔细胞产生促炎细胞因子 TNF-α 和 IL-1β 的最有效肽，但对抗炎细胞因子 IL-10 的产生没有影响。Phylloseptin-2.1TR 和 phylloseptin-3.3TR 最有效地刺激 IL-10 的产生。非细胞毒性肽 plastin-TR 抑制 TNF-α 和 IL-1β 的产生，但对 IL-10 的产生没有影响。圆二色性（CD）光谱的结果表明，与之前表征的来自 Leptodactylus laticeps 的免疫刺激活性的 plastin-L1 相比，plasticin-TR 的不同性质可能源于其更大的寡聚化能力和在模拟膜环境中采用稳定的螺旋构象的能力。所有肽均刺激 BRIN-BD11 大鼠克隆β细胞释放胰岛素，其中 phylloseptin-3.2TR 最有效，phylloseptin-2.1TR 最无效，这表明胰岛素促泌活性与螺旋性呈负相关。该研究深入了解了 phylloseptin 之间的结构-活性关系。免疫调节和胰岛素促泌活性与低细胞毒性相结合表明，phylloseptin-3.3TR 和 plastin-TR 可能代表用于抗炎和 2 型糖尿病治疗的制剂开发的模板。
