Complexation potentiated promising anti-diabetic and anti-oxidative synergism between ZN(ii) and ferulic acid: A multimode study

Aim: This study was done to investigate the anti-diabetic and anti-oxidative synergism between zinc(II) and ferulic acid through complexation. Methods: Zinc sulphate was complexed with ferulic acid in a 1:2 molar ratio. The complex was characterized using Fourier-transform infrared spectroscopy, proton NMR and high-resolution mass spectroscopy techniques and evaluated for cellular toxicity. In silico, in vitro, cell-based and tissue experimental models were used to test the anti-diabetic and anti-oxidant activities of the complex relative to its precursors. Results: A zinc(II)-biferulate(center dot)2H(2)O complex was formed. The in vitro radical scavenging, anti-lipid peroxidative and alpha-glucosidase and alpha-amylase inhibitory activity of the complex was 1.7-2.1 folds more potent than ferulic acid. Zn(II) complexation increased the anti-glycation activity of ferulic acid by 1.5 folds. The complex suppressed lipid peroxidation (IC50 = 48.6 and 331 mu M) and GHS depletion (IC50 = 33.9 and 33.5 mu M) in both Chang liver cells and isolated rat liver tissue. Its activity was 2.3-3.3 folds more potent than ferulic acid and statistically comparable to ascorbic acid. Zn(II) complexation afforded ferulic acid improved glucose uptake activity in L-6 myotube (EC50 = 11.7 vs. 45.7 mu M) and isolated rat muscle tissue (EC50 = 501 and 1510 mu M). Complexation increased muscle tissue zinc(II) uptake and hexokinase activity. Docking scores of the complex (-7.24 to -8.25 kcal/mol) and ferulic acid (-5.75 to 6.43 kcal/mol) suggest the complex had stronger interaction with protein targets related to diabetes, which may be attributed to the 2 ferulic acid moieties and Zn(II) in the complex. Moreover, muscle tissue showed increased phospho-Akt/pan-Akt ratio upon treatment with complex. The complex was not hepatotoxic and myotoxic at in vitro cellular level. Conclusion: Zn(II) complexation may be promising therapeutic approach for improving the glycaemic control and anti-oxidative potential of natural phenolic acids.