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

Godfrey R Matowane; Limpho M Ramorobi; Samson S Mashele; Susanna L Bonnet; Anwar E M Noreljaleel; Shasank S Swain; Tshepiso J Makhafola; Chika I Chukwuma

doi:10.1111/dme.14905

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

Diabet Med. 2022 Sep;39(9):e14905. doi: 10.1111/dme.14905. Epub 2022 Jul 6.

Authors

Godfrey R Matowane^{1

2}, Limpho M Ramorobi^{1

2}, Samson S Mashele^{1

2}, Susanna L Bonnet³, Anwar E M Noreljaleel³, Shasank S Swain⁴, Tshepiso J Makhafola², Chika I Chukwuma²

Affiliations

¹ Department of Health Sciences, Faculty of Health and Environmental Sciences, Central University of Technology, Bloemfontein, Free State, South Africa.
² Centre for Quality of Health and Living (CQHL), Faculty of Health and Environmental Sciences, Central University of Technology, Bloemfontein, Free State, South Africa.
³ Department of Chemistry, Faculty of Natural and Agricultural Sciences, University of the Free State, Bloemfontein, South Africa.
⁴ Division of Microbiology & NCDs, ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, India.

PMID: 35748705
DOI: 10.1111/dme.14905

Abstract

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.

Keywords: diabetes; experimental pharmacology; oxidative stress; therapeutics; zinc(II)-ferulic acid complexation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Coumaric Acids / chemistry
Coumaric Acids / pharmacology
Coumaric Acids / therapeutic use
Diabetes Mellitus* / drug therapy
Humans
Proto-Oncogene Proteins c-akt* / metabolism
Rats
Zinc / chemistry
Zinc / pharmacology

Substances

Coumaric Acids
ferulic acid
Proto-Oncogene Proteins c-akt
Zinc