Bioactive synergism between zinc mineral and p-coumaric acid: A multi-mode glycemic control and antioxidative study

Natural supplements are important in diabetes and oxidative stress management. A complexation-mediated antihyperglycemic and antioxidant synergism between zinc(II) and p-coumaric acid was investigated. p-Coumaric acid was complexed with ZnSO₄ and characterized by FT-IR, ¹ H NMR, and mass spectroscopy. The antioxidant and antihyperglycemic potential of the complex and precursors were evaluated with different experimental models. Molecular docking with target proteins linked to diabetes was performed. A Zn(II)-bicoumarate.2H₂ O complex was formed. The in vitro radical scavenging, α-glucosidase inhibitory, antiglycation, and anti-lipid peroxidative activities of the complex were several folds stronger than p-coumaric acid. In Chang liver cells and rat liver tissues, the complex inhibited lipid peroxidation (IC₅₀  = 56.2 and 398 μM) and GSH depletion (IC₅₀  = 33.9 and 38.7 μM), which was significantly stronger (2.3-5.4-folds) than p-coumaric acid and comparable to ascorbic acid. Zn(II) and p-coumaric synergistically modulated (1.7- and 2.8-folds than p-coumaric acid) glucose uptake in L-6 myotubes (EC₅₀  = 10.7 μM) and rat muscle tissue (EC₅₀  = 428 μM), which may be linked to the observed complexation-mediated increase in tissue zinc uptake. Glucose uptake activity was accompanied by increased hexokinase activity, suggesting increased glucose utilization. Docking scores α-glucosidase, GLUT-4, and PKB/Akt showed stronger interaction with the complex (-6.31 to -6.41 kcal/mol) compared to p-coumaric acid (-7.18 to -7.74 kcal/mol), which was influenced by the Zn(II) and bicoumarate moieties of the complex. In vitro, the complex was not hepatotoxic or myotoxic. Zn(II) complexation may be a therapeutic approach for improving the antioxidative and glycemic control potentials of p-coumaric acid. PRACTICAL APPLICATIONS: In functional medicine, natural supplements, plant-derived phenolics, and nutraceuticals are becoming popular in the management of diseases, including diabetes and oxidative stress. This has been largely attributed to their perceived holistic medicinal profile and the absence of notable toxicity concerns. In the past two decades, considerable attention has been drawn toward zinc mineral as a possible therapeutic supplement for diabetes due to its role in insulin secretion and reported insulin mimetic potentials. p-Coumaric acid is a known natural antioxidant with reported diabetes-related pharmacological effects. In this study, we took advantage of these properties and complexed both natural supplements, which resulted in a more potent nutraceutical with improved glycemic control and antioxidant potential. The complexation-mediated synergistic interaction between zinc and p-coumaric acid could be an important therapeutic approach in improving the use of these natural supplements or nutraceuticals in managing diabetes and associated oxidative complications.