Department of Pharmaceutical Chemistry, Faculty of Pharmacy, International Islamic University Malaysia, Kuantan 25200, Pahang DM, Malaysia.
Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
Biomolecules. 2018 Nov 15;8(4):149. doi: 10.3390/biom8040149.
Flavonoids have been reported to exert antihyperglycemic effects and have potential to enhance the current therapy options against type 2 diabetes mellitus. However, the structure activity relationships (SAR) studies of flavonoids against this disease have not been thoroughly comprehended. Hence, in the present study, 14 structurally related flavonoids viz. wogonin, techtochrysin, norwogonin, isoscutellarein, hypolaetin, kaempferol, quercetin, methyl ether of wogonin, acetate of wogonin, acetate of norwogonin, 8-hydroxy-7-methoxyflavone, chrysin, (+)-catechin and (-)-epicatechin were taken into account for in vitro antidiabetic evaluation. Cell viability of RIN-5F pancreatic cells and 3T3-L1 pre-adipocyte cells was initially tested, then an insulin secretion assay of RIN-5F as well as adipogenesis and glucose uptake measurements of adipocyte were investigated. Subsequently, protein expressions study through adipokines measurement (leptin, adiponectin, TNF-α, RBP-4) via enzyme-linked immunosorbent assay (ELISA) kit, Western blotting analysis against GLUT4 and C/EBP-α as well as molecular docking against GLUT1 were analyzed. The results from cell culture antidiabetic assays (insulin secretion, adipogenesis, and glucose uptake), protein expressions and molecular docking pointed that the methoxy group at position C-8 is responsible for antidiabetic property of selected flavonoids via glucose uptake mechanism indicated by up regulation of GLUT4 and C/EBP-α expressions. The mechanism could be enhanced by the addition of an acetate group at C-5 and C-7 of the flavone skeleton.
类黄酮已被报道具有抗高血糖作用，并有可能增强当前 2 型糖尿病的治疗选择。然而，类黄酮对这种疾病的构效关系（SAR）研究尚未得到彻底理解。因此，在本研究中，考虑了 14 种结构相关的类黄酮，即：黄岑素、白杨素、桑根酮 D、异桑根素、高良姜素、山奈酚、槲皮素、黄岑素甲醚、黄岑素乙酸酯、桑根酮 D 乙酸酯、8-羟基-7-甲氧基黄酮、白杨素、（+）-儿茶素和（-）-表儿茶素，用于体外抗糖尿病评价。首先测试了 RIN-5F 胰腺细胞和 3T3-L1 前脂肪细胞的细胞活力，然后进行了 RIN-5F 的胰岛素分泌测定以及脂肪生成和葡萄糖摄取测量。随后，通过酶联免疫吸附测定（ELISA）试剂盒测量脂肪细胞的脂肪因子表达（瘦素、脂联素、TNF-α、RBP-4），通过 Western blot 分析针对 GLUT4 和 C/EBP-α 以及针对 GLUT1 的分子对接进行蛋白表达研究。细胞培养抗糖尿病测定（胰岛素分泌、脂肪生成和葡萄糖摄取）、蛋白表达和分子对接的结果表明，C-8 位的甲氧基是通过上调 GLUT4 和 C/EBP-α 表达来实现所选类黄酮的抗糖尿病特性的原因。该机制可以通过在黄酮骨架的 C-5 和 C-7 位添加乙酸基来增强。
