| 兰莹,郝翠,张丽娟.聚甘露糖醛酸硫酸酯及寡糖在表达FGFR1c的BaF3细胞中可激活FGF1/19/21信号通路[J].中国海洋药物,2017,36(1):1-6. |
| 聚甘露糖醛酸硫酸酯及寡糖在表达FGFR1c的BaF3细胞中可激活FGF1/19/21信号通路 |
| Polymannuronate Sulfate and its Oligosaccharides Activates FGF1, FGF19, and FGF21 Signaling in FGFR1c-Expressing BaF3 Cells |
| 投稿时间：2016-06-05 修订日期：2016-07-09 |
| DOI： |
| 中文关键词: 聚甘露糖醛酸硫酸酯 聚甘露糖醛酸硫酸酯寡糖 成纤维细胞生长因子(FGF) 成纤维细胞生长因子受体(FGFR) 糖尿病 |
| English Keywords:polymannuronate sulfate polymannuronate sulfate oligosaccharide fibroblast growth factor fibroblast growth factor receptor diabetes |
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| 中文摘要: |
| 目的 近几年来发表的数据显示成纤维细胞生长因子(FGFs),包括FGF1, FGF19和FGF21, 具有类似于胰岛素的代谢调节功能。例如,在饮食诱导的糖尿病小鼠中,FGF1的单次注射足以使血糖水平恢复到正常范围；同时FGF19或FGF21过表达可以校正糖耐量受损的小鼠。在细胞表面,FGFs通过FGF受体(FGFR)和糖胺聚糖进行信号传导。FGF1与属于糖胺聚糖的肝素具有高亲和力,而FGF19和FGF21与肝素无亲和力。糖胺聚糖结构多样,是信息含量最高的生物大分子。我们认为如果非肝素类多糖可以刺激FGF19/FGFR和FGF21/FGFR的信号传导,这类化合物有可能成为调节代谢疾病的新型药物。方法 我们采用表达FGFR1c的BaF3细胞作为筛选具有活性多糖与寡糖的模型。结果 发现聚甘露糖醛酸硫酸酯(PMS)及寡糖(PMS12及PMS25)可以增强FGF19和FGF21介导下的BaF3细胞中 3H-胸苷嘧啶标记的DNA合成,而聚甘露糖醛酸(PM)无此作用。此外,PMS,PMS寡糖包括其二糖与肝素类似具有增强FGF1/FGFR1c信号通路介导的BaF3的细胞增殖作用。结论 由于PMS及其寡糖可通过口服途径被吸收,因此这些廉价的海藻酸衍生物有可能通过增强FGF1/FGFR1c,FGF19/FGFR1c和FGF21/FGFR1c的信号传导而被开发成为治疗2型糖尿病的新型口服药物。 |
| English Summary: |
| Objective Fibroblast growth factors (FGFs) including FGF1, FGF19, and FGF21 regulate metabolic functions in a way similar to that of insulin. For example, in mice with diet-induced diabetes, a single injection of FGF1 is enough to restore blood sugar level to a healthy range whereas over-expressing FGF19 or FGF21 in mice also corrects impaired glucose tolerance. FGFs signal through FGF receptors (FGFRs) and glycosaminoglycans. Interestingly, FGF1 binds heparin with high affinity whereas FGF19 and FGF21 do not, indicating other polysaccharides other than heparin might enhance FGF19/FGFR and FGF21/FGFR signaling. Methods We used a FGF/FGFR1c signaling-dependent BaF3 cell proliferation assay to screen poly- and oligosaccharides that could activate FGF/FGFR signaling. Results We discovered that polymannuronate sulfate (PMS) and its oligosaccharides, PMS12 and PMS25, but not polymannuronate (PM), a natural marine polysaccharide, enhanced FGF19/FGFR1c and FGF21/FGFR1c signaling better than that of heparin based on 3H-thymidine incorporation in FGFR1c-expressing BaF3 cells. In addition, PSM and PMS oligosaccharides including its sulfated disaccharides, but not PM, had FGF1/FGFR1c signal-stimulating activity similar to that of heparin. Conclusions Our results indicated that PMS and its oligosaccharides were excellent FGF1/FGFR1c, FGF19/FGFR1c, and FGF21/FGFR1c signaling enhancers at cellular level. Since the inexpensive PMS and its oligosaccharides can be absorbed through oral route, these seaweed-derived compounds were interesting agents that might be useful for treating type 2 diabetes through enhancing FGF1/FGFR1c, FGF19/FGFR1c, and FGF21/FGFR1c signaling in near future. |
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