The ameliorative effect of zinc acetate with caffeic acid in the animal model of type 2 diabetes.

Recently the complexation-mediated antioxidative and glycaemic control synergism between zinc(II) and caffeic acid was demonstrated in vitro. The present study evaluated the complexation-mediated antidiabetic and antioxidative synergism between zinc(II) and caffeic acid in diabetic rats and the possible underlying mechanisms. Male SD rats were induced with diabetes using 10% fructose and 40 mg/kg bw streptozotocin. The diabetic rats were treated with Zn(II)-caffeic acid complex and its precursors (caffeic acid and zinc acetate) for 4 weeks at predetermined doses. The effect of the treatments on diabetes and oxidative stress was measured. The complex ameliorated diabetic alterations. It reduced polyphagia and polydipsia and recovered weight loss. It increased insulin secretion, insulin sensitivity, hepatic and muscle glycogen, muscle hexokinase activity and Akt phosphorylation, which resulted in improved glucose tolerance and reduced blood glucose in the diabetic rats. The complex concomitantly reduced systemic and tissue lipid peroxidation and increased antioxidant enzymes activity in the diabetic rats. The complex outperformed the antidiabetic and antioxidative action of its precursors and had a broader bioactivity profile. Complexing zinc acetate with caffeic acid improved their ameliorative effect on insulin resistance by ∼24% and 42%, respectively, as well as their anti-hyperglycaemic action by ∼24 - 36% and ∼42 - 47%, respectively, suggesting a complexation-mediated synergism. In some instances, the antidiabetic action of the complex was comparable to metformin, while its antioxidant effect was better than that of metformin. Zinc(II)-caffeic acid complexation may be an alternative approach to improving the efficacy of antidiabetic and antioxidative therapy with minimal adverse or side effects.

Novel Caffeic Acid - Zinc Acetate Complex: Studies on Promising Antidiabetic and Antioxidative Synergism Through Complexation.

BACKGROUND: The role of Zn(II) in storage, insulin secretion and function has been documented, while plant phenolics have antioxidant and other pharmacological credence. OBJECTIVE: The study aimed at synthesizing a novel medicinal Zn(II) complex. The medicinal properties of zinc(II) and caffeic acid were considered in synthesizing a novel complex with promising and improved antioxidant and anti-hyperglycaemic attributes. METHODS: Complex synthesis was done using a 1:2 molar ratio of zinc acetate and caffeic acid and structurally characterized using NMR, FT-IR, high resolution-mass spectroscopy and HPLC. Its cellular toxicity was assessed in Chang liver cells and L-myotubes. In vitro, cellular, and isolated tissue models were used to evaluate the antioxidant and anti-hyperglycaemic properties of the complex relative to its precursors. Molecular docking was used to investigate the interaction with insulin signalling target proteins: GLUT-4 and protein kinase B (Akt/PKB). RESULTS: Zinc(II) and caffeic acid interacted via Zn:O4 coordination, with the complex having one moiety of Zn(II) and 2 moieties of caffeic acid. The complex showed in vitro radical scavenging, α- glucosidase and α-amylase inhibitory activity up to 2.6 folds stronger than caffeic acid. The ability to inhibit lipid peroxidation (IC50 = 26.4 µM) and GSH depletion (IC50 = 16.8 µM) in hepatocytes was comparable to that of ascorbic acid (IC50 = 24.5 and 29.2 µM) and about 2 folds stronger than caffeic acid. Complexation improved glucose uptake activity of caffeic acid in L-6 myotubes (EC50 = 23.4 versus 169 µM) and isolated rat muscle tissues (EC50 = 339 versus 603 µM). Molecular docking showed better interaction with insulin signalling target proteins (GLUT-4 and Akt/PKB) than caffeic acid. The complex was not hepatotoxic or myotoxic. CONCLUSION: Data suggest a synergistic antioxidant and anti-hyperglycaemic potential between zinc and caffeic acid, which could be attributed to the Zn:O4 coordination. Thus, it may be of medicinal relevance.

Zinc(II) - Syringic acid complexation synergistically exerts antioxidant action and modulates glucose uptake and utilization in L-6 myotubes and rat muscle tissue.

Zinc and syringic acid have metabolic and antioxidant medicinal potentials. A novel zinc(II)-syringic acid complex with improved anti-hyperglycaemic and antioxidant potential was developed. Zinc(II) was complexed with syringic acid in a 1:2 molar ratio and characterized using FT-IR, 1H NMR and LC-MS. Different experimental models were used to compare the anti-hyperglycaemic and antioxidant properties between the complex and precursors. A Zn(II)-bisyringate.2H2O complex was formed. The in vitro radical scavenging and Fe3+ reducing antioxidant, antiglycation, and α-glucosidase inhibitory activities of the complex were 1.8-5.2 folds stronger than those of the syringic acid precursor and comparable to those of the positive controls. The complex possessed an increased ability to inhibit lipid peroxidation (by 1.6-1.7 folds) and glutathione depletion (2.8-3 folds) relative to syringic acid in Chang liver cells and liver tissues isolated from rats. The complex exhibited a higher glucose uptake effect (EC50 = 20.4 and 386 µM) than its precursors (EC50 = 71.1 and 6460 µM) in L6-myotubes and psoas muscle tissues isolated from rats, respectively, which may be linked to the observed increased cellular zinc uptake potentiated by complexation. Tissue glucose uptake activity was accompanied by increased hexokinase activity, suggesting increased glucose utilization. Moreover, treatment increased tissue phospho-Akt/pan-Akt ratio. The complex had strong molecular docking scores than syringic acid with target proteins linked to diabetes. The presence of two syringic acid moieties and Zn(II) in the complex influenced its potency. The complex was not hepatotoxic and myotoxic in vitro. Zinc-syringic acid complexation may be a novel promising therapeutic approach for diabetes and oxidative complications.

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.

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.2H2 O complex was formed. The in vitro radical scavenging, anti-lipid peroxidative and α-glucosidase and α-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 µM) and GHS depletion (IC50  = 33.9 and 33.5 µM) 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 µM) and isolated rat muscle tissue (EC50  = 501 and 1510 µM). 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.

Zinc(II) mineral increased the in vitro, cellular and ex vivo antihyperglycemic and antioxidative pharmacological profile of p-hydroxybenzoic acid upon complexation.

In this study, zinc was complexed with p-hydroxybenzoic acid to synthesize a complex with improved pharmacological profile. Proton NMR and FTIR analysis were used to characterize the complex. Several in vitro, cellular and ex vivo antihyperglycemic and antioxidative assays were used to evaluate the potency of the complex, relative to its precursors, while molecular docking was used to investigate interactions with insulin signaling targets (GLUT-4 and PKB). Also, the cytotoxicity of the complex was evaluated in Chang liver cells and L-6 myotubes using MTT assay. Complexation was through a Zn(O4 ) coordination. This afforded the complex two moieties of p-hydroxybenzoic acid, which influenced its activities. While the complex retained the α-glucosidase and α-amylase inhibitory activity of its phenolic acid precursor, complexation increased in vitro and ex vivo antioxidant activity of the phenolic acid by 1.4 to 10.5-folds. Complexation, further, conferred a potent antiglycation activity and L-6 myotube and psoas muscle glucose uptake properties (2.1 to 3.5-folds more than p-hydroxybenzoic acid) on the phenolic acid, without notably inhibiting or reducing the viability of Chang liver cells (IC50  = 5,120 µM) and L-6 myotubes (IC50  = 2,172 µM). Docking studies showed the complex had better interactions with insulin signaling targets (GLUT-4 and PKB) than p-hydrobenzoic acid, which may influence its glucose uptake effects. Data suggest that Zn(II) complexation improved and/or broadened the pharmacological profile of p-hydroxybenzoic acid, thus, may be further studied as a promising adjuvant for phenolic acids. PRACTICAL APPLICATIONS: Most antidiabetic drugs are used as two or more combinations to achieve better efficacy, which may cause drug interaction and increase the risk of side effects associated with these drugs. This study takes advantage of the glycemic control property of zinc and the antioxidant and/or diabetes-related pharmacological properties of p-hydroxybenzoic acid to form a complex with improved and broader antioxidant and antihyperglycemic profile and minimal toxicity concerns. With appropriate further studies, Zn(II)-phenolic acid complexes may be safe nutraceuticals for diabetes and related oxidative complications.

Synthesis, characterization, antidiabetic and antioxidative evaluation of a novel Zn(II)-gallic acid complex with multi-facet activity.

OBJECTIVES: This study was done to synthesize a novel Zn(II)-gallic acid complex with improved antidiabetic and antioxidative properties. METHODS: The complex was synthesized and characterized using Fourier Transform Infrared (FT-IR) and 1 H NMR. Cytotoxicity was evaluated using Chang liver cells and L6 myotubes. Radical scavenging and Fe3+ -reducing, as well as α-glucosidase, α-amylase and glycation inhibitory properties were measured. Glucose uptake was measured in L6 myotubes, while the complex was docked against glucose transporter type 4 (GLUT-4) and protein kinase B (PKB). KEY FINDINGS: Analysis showed that complexation occurred through a Zn(O4 ) coordination; thus, the complex acquired two moieties of gallic acid, which suggests why complexation increased the DPPH (IC50  = 48.2 µm) and ABTS (IC50  = 12.7 µm) scavenging and α-glucosidase inhibitory (IC50  = 58.5 µm) properties of gallic acid by several folds (5.5, 3.6 and 2.7 folds; IC50  = 8.79, 3.51 and 21.5 µm, respectively). Zn(II) conferred a potent dose-dependent glucose uptake activity (EC50  = 9.17 µm) on gallic acid, without reducing the viability of L6 myotubes and hepatocytes. Docking analysis showed the complex had stronger interaction with insulin signalling proteins (GLUT-4 and PKB) than its precursor. CONCLUSIONS: Data suggest that complexation of Zn(II) with gallic acid resulted in a complex with improved and multi-facet antioxidative and glycaemic control properties.

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.