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.

Vanillic acid-Zn(II) complex: a novel complex with antihyperglycaemic and anti-oxidative activity.

OBJECTIVES: Our aim was to synthesize, characterize and evaluate the antihyperglycaemic and anti-oxidative properties of a new Zn(II) complex of vanillic acid. METHODS: The complex was synthesized using ZnSO4.7H2O and vanillic acid as precursors. NMR and FTIR techniques were used to characterize the synthesized complex. The cytotoxicity of the complex was measured. The antihyperglycemic and anti-oxidative properties of the complex were evaluated using in vitro, cell-based and ex vivo models and compared with those of its precursors. KEY FINDINGS: Zn(II) coordinated with vanillic acid via a Zn(O6) coordination, with the complex having three moieties of vanillic acid. The radical scavenging, Fe3+ reducing and hepatic antilipid peroxidative activity of the complex were, respectively, 2.3-, 1.8- and 9.7-folds more potent than vanillic acid. Complexation increased the α-glucosidase and glycation inhibitory activity of vanillic acid by 3- and 2.6-folds, respectively. Zn(II) conferred potent L-6 myotube (EC50 = 20.4 µm) and muscle tissue (EC50 = 612 µm) glucose uptake effects on vanillic acid. Cytotoxicity evaluation showed that the complex did not reduce the viability of L-6 myotubes and Chang liver cells. CONCLUSIONS: The data suggest that Zn(II)-vanillic acid complex had improved bioactivity relative to vanillic acid. Thus, Zn(II) may be further studied as an antihyperglycaemic and anti-oxidative adjuvant for bioactive phenolic acids.

A comprehensive review on zinc(II) complexes as anti-diabetic agents: The advances, scientific gaps and prospects.

Zinc has gained notable attention in the development of potent anti-diabetic agents, due to its role in insulin storage and secretion, as well as its reported insulin mimetic properties. Consequently, zinc(II) has been complexed with numerous organic ligands as an adjuvant to develop anti-diabetic agents with improved and/or broader scope of pharmacological properties. This review focuses on the research advances thus far to identify the major scientific gaps and prospects. Peer-reviewed published data on the anti-diabetic effects of zinc(II) complexes were sourced from different scientific search engines, including, but not limited to "PubMed", "Google Scholar", "Scopus" and ScienceDirect to identify potent anti-diabetic zinc(II) complexes. The complexes were subcategorized according to their precursor ligands. A critical analysis of the outcomes from published studies shows promising leads, with Zn(II) complexes having a "tri-facet" mode of exerting pharmacological effects. However, the promising leads have been flawed by some major scientific gaps. While zinc(II) complexes of synthetic ligands with little or no anti-diabetic pharmacological history remain the most studied (about 72 %), their toxicity profile was not reported, which raises safety concerns for clinical relevance. The zinc(II) complexes of plant polyphenols; natural ligands, such as maltol and hinokitiol; and supplements, such as ascorbic acid (a natural antioxidant), l-threonine and l-carnitine, showed promising insulin mimetic and glycemic control properties but remain understudied and lack clinical validation, in spite of their minimal safety concerns and health benefits. A paradigm shift toward probing (including clinical studies) supplements, plant polyphenol and natural ligands as anti-diabetic zinc(II) complex is, therefore, recommended. Also, promising anti-diabetic Zn(II) complexes of synthetic ligands should undergo critical toxicity evaluation to address possible safety concerns.